From 93d862046ce852d5f574b912f006b2ff7d34dcd0 Mon Sep 17 00:00:00 2001 From: ackman678 Date: Wed, 28 Oct 2020 21:56:06 -0700 Subject: [PATCH] into neurotrans --- neuroanatomy1.md | 331 +++++----- neuroanatomy2.md | 51 +- neurophysiology1.md | 80 +-- neurophysiology2.md | 65 +- neurophysiology3.md | 6 +- neurophysiology4.md | 12 - neurotransmitters1.md | 1359 ++++++++++++++--------------------------- neurotransmitters2.md | 1319 +++++++++++++++++++++++++-------------- 8 files changed, 1635 insertions(+), 1588 deletions(-) diff --git a/neuroanatomy1.md b/neuroanatomy1.md index cef8d90..96089fa 100644 --- a/neuroanatomy1.md +++ b/neuroanatomy1.md @@ -4,7 +4,12 @@ Neuroscience is a field of scientific study that seeks to understand how the ner -https://canvas.ucsc.edu/courses/25273 +https://canvas.ucsc.edu/courses/36780 + +
+ +
+ Note: Welcome. This class will be an Introduction to Neuroscience– @@ -13,15 +18,15 @@ Neuroscience is a field that by necessity integrates information and techniques And ultimately it is a field of science that seeks to understand how this lump of biological tissue siting inside our heads has evolved the capability of asking questions about its own nature and existence. -While humankind has learned alot about nervous system structure and function, there is a great deal left to understand. It's up to you to figure it all out. +"carries out *its* **functions**" + -Thus it will be you, and your children, and your children’s children that will figure it all out and literally allow human beings to reach the stars. -- ## Syllabus and text book -
https://canvas.ucsc.edu/courses/16047/assignments/syllabus
+
https://canvas.ucsc.edu/courses/16047/assignments/syllabus
5e 2011
@@ -45,7 +50,7 @@ Thus it will be you, and your children, and your children’s children that will -Recommend browser is Firefox or Chrome on a laptop/PC. Some features that only have keyboard bindings (e.g. fullscreen, overview) may not work or be disabled on tablet/touch screen devices. +Recommend browser is Firefox or Chromium on a laptop/PC. Some features that only have keyboard bindings (e.g. fullscreen, overview) may not work or be disabled on tablet/touch screen devices. @@ -74,53 +79,55 @@ Therefore the brain’s functions are dynamic, vast and wide ranging, and extend
J. Haldeman, 1974
- +
Futurama, 2008. 'Where no fan has gone before'
Note: Ever since the dawn of the industrial age in the mid 19th century and Jules Verne's 1865 novel 'From the Earth to the Moon' humans have been dreaming of the future, not just here but among the stars. And those futures can become reality like when the Apollo astronauts landed on the moon and acknowledged the inspiration that Verne's orig sci-fi novel had on many. -Neuroscience and its role for proper physiological function is going to play a role in many advances in health and technology for humankind now and far into the future-- +* Neuroscience and its role for proper physiological function is going to play a role in many advances in health and technology for humankind now and far into the future-- -To reach the stars we will need: +* To reach the stars we will need: - robots, artificial intelligence, I. Asimov Philip K. Dick's 1968 novel 'Do Androids Dream of Electric Sheep' - virtual reality, brain machine interfaces, James Cameron's Avatar - medical tricorders, 1960s series Star Trek - physiological stasis, cryopreservation, waking up the brain space after travel like Joe Haldeman's 1974 novel 'The Forever War' or the Ridley Scott's movie Aliens -The human brain and its limitless creativity has packed a bunch of computational power into this little device in our pocket. And yet this device is really just made up of lots of simple little semiconductive elements. The human brain even invented this masking tape that currently holds together my broken phone. So what is the atomic unit of our brains function and how is it structured to achieve our cognitive abilities and our consciousness? We will find the answers to some of these question in this course, but will also discover as is usually the case when looking into nature's secrets that we humbly know so little. +The human brain and its limitless creativity has packed a bunch of computational power into this little device in our pocket. And yet this device is really just made up of lots of simple little semiconductive elements. So what is the atomic unit of our brains function and how is it structured to achieve our cognitive abilities and our consciousness? We will find the answers to some of these question in this course, but will also discover as is usually the case when looking into nature's secrets that we humbly know so little. -Or futures that seem impossibly fanciful but who knows 10k or 100k years, maybe consciousness will be woven into some sort of singular virtual world like in the matrix or the cylons from Battle Star Galactica. +Or perhaps a discomforting future where maybe consciousness will be woven into some sort of singular virtual world like in the matrix or the cylons from Battlestar Galactica in ten or ten thousand years? -think of virtual reality which is now almost a reality, can we solve the mismatches between sensory information and body positioning to get rid of the nausea associated with this technology? Think of artifical intelligence and robotics +Think of virtual reality which is now almost a reality, can we solve the mismatches between sensory information and body positioning to get rid of the nausea associated with this technology? Think of artifical intelligence and robotics -If we will be traveling through space we will need to keep our bodies disease free to get wherever we are going-- will be know enough about brain function and neurolgical disease to fix things on the fly with a medical tricorder device like in Star Trek? - -Can we read the minds of a suspect in a courtroom with a brain imaging device? Do we even want to do that? Think of Can we rid - -The human brain and its limitless creativity has packed a bunch of computational power into this little device in our pocket. And yet this device is really just made up of lots of simple little semiconductive elements. The human brain even invented this masking tape that currently holds together my broken phone. So what is the atomic unit of our brains function and how is it assembled to achieve our cognitive abilities? We will find the answers to some of these question in this course, but will also discover as is usually the case when looking into nature's secrets that we know so little. +If we will be traveling through space (well technically we are already traveling through space;) we will need to keep our bodies disease free to get wherever we are going-- will we know enough about brain function and neurolgical disease to fix things on the fly with a medical tricorder device like in Star Trek? +Can we read the minds of a suspect in a courtroom with a brain imaging device? Do we even want to do that? Since that time we've dreamed up fantastical futures in shows like Star Trek and the Jetsons and dystopian ones in Blade Runner and the Terminator or even ones past (for example think "long time ago in a galaxy far far away...") -Many of things dreamed of are already presentImagine some of things thought of and now already present flying aeroplanes, personal landspeeders, rocket ships to distant planets +Some of the **things** dreamed of are already present. Flying aeroplanes, personal landspeeders, rocket ships to distant planets, autonomous-automobiles. -- Edgar Rice Burroughs John Carter thought waves example. -Penfield mood organ +- Edgar Rice Burroughs A Priestess of Mars: John Carter hurling thought waves. +- Do Androids Dream of Electric Sheep: Penfield mood organ +* So is the nervous system then a device for + - detecting physiological change? + - seeking pleasurable rewards? a dopamine machine? + - navigating space + time? + - processing emotional secretions? --- -## We will focus on a few basic features of the nervous system - -* The mechanisms by which neurons produce signals -* The patterns of connections between nerve cells -* The relationship of different patterns of interconnections to different types of behavior +## Questions to keep in *mind* as we study neuroscience now and beyond +* What signals are produced by a nervous system? How? Why? +* How are input stimuli from the external or internal environment transduced by the nervous system? +* Where and how does sensor input get tranformed into a behavioral decision and an output pattern to be actuated? +* What is a structure? What is a function? Note: @@ -143,6 +150,142 @@ sinew --- + +## What are brains made of? + +A glob of squishy jello? + +
+ +
+ +
Wikimedia Commons
+ +Cells. (though jello is made of collagen...) + +Note: + +So what are brains made of? Anybody? Jello? What is this 1.5 kg or 3 lb human brain made of? + +Yes it is soft and squishy but it is not just a gelanitous mass like jello. Shown here is a section through a human brain. It is about 20 cm long and if we were to zoom in on a tiny part of it and use a special dye and microscope what we see is that the brain is made of cells. So this is a pyramidal neuron in from the cerebral cortex and its cell body is about 30-40µm in diameter. + +--- + +## Brains are made of cells + +* Camillo Golgi (Italy)– believed that cells in the brain were directly connected forming a **continuous network** (reticular theory). +* Santiago Ramon y Cajal (Spain)– Brains made up of single cells and communicate at specialized areas called synapses. +* Shared Nobel prize in 1906 + +Note: + +Seems fairly obvious now. But wasn't in the 19th c. Cells widely accepted everywhere else in the 1830’s. But neuroscientists were the last to accept this right up until the turn of the 20th c. + +Only after fundamental and rigorous work by these two scientists, C. Golgi and S. Ramon y Cajal in the late 19th c. did we come to appreciate comprised of individual cellular elements rather than a continous network or syncytium. + +--- + +## Golgi staining + +Golgi staining: potassium chromate and silver nitrate (1873) + +
Golgi's drawing of the hippocampus impregnated by his stain
from Golgi's Opera Omnia.
+ +
Golgi's drawing of hippocampal dentate gyrus
fig. 9 from Golgi's Nobel lecture
+ + +Note: + +Golgi's drawing of hippocampus after performing his black potassum chromate and silver nitrate stain. Bottom is a zoomed in drawing of neurons and their connections in the hippocampal dentate gyrus. + +--- + +## The nervous system is not a syncytium + +* syncytium: a mass of cytoplasm with many nuclei but no internal cell boundries +* reticulum: a fine network or netlike structure +* Camillo Golgi, Nobel Lecture December 11, 1906, *The Neuron Doctrine- theory and facts*: + +
+
+ +>"...Far from being able to accept the idea of the individuality and independence of each nerve element, I have never had reason, up to now, to give up the concept which I have always stressed, that nerve cells, instead of working individually, act together, so that we must think that several groups of elements exercise a cumulative effect on the peripheral organs through whole bundles of fibers." + +
+ +Note: + +Golgi drew the structure of the hippocampus as being all fused together into a reticulum, no free axon endings + +Syncytiums are important in living organisms. From the placenta at the beginning of your existence to your multinucleated myocytes and osteocytes that make up your muscle and bones as you chase the Pacific Sun, syncytiums always play an important role. + +--- + +## The Neuron Doctrine + +* Santiago Ramon y Cajal +* Neurons are cells. Each is an *individual entity* anatomically, embryologically, and functionally. +* Neurons have a functional polarity + +
Cajal drawing of golgi stained retina. Cells are separate units and arrows indicate direction of information flow.
+ + +Note: + +Neurons in culture have specific endings. EM methods, dye filling experiments. + +Heinrich Wilhelm Gottfried von Waldeyer-Hartz (6 October 1836 – 23 January 1921) was a German anatomist and conceived the word 'neuron'. + +Golgi in his nobel lecture: + +>(3) The neuron is a physiological unit. This fundamental idea which Waldeyer expressed with perfect precision has been enlarged upon both from anatomical and functional sides with additional propositions, for example : **The communication between neurons is only established by casual contact. There is scarcely any nervous tissue apart from the neurons; the neurons are also trophic units.** + +individual entitites. boxes within boxes. containers. + +--- + +## The Nobel Prize in Physiology or Medicine 1906 + +>"in recognition of their work on the structure of the nervous system" + +
+ +Camillo Golgi +Pavia University +Pavia, Italy + +
+ +
+ +Santiago Ramón y Cajal +Madrid University +Madrid, Spain + +
+ + +Note: + +--- + +## How many neurons in a human brain? + +* 100 thousand +* 10 million +* 100 million +* 1 billion +* 10 billion +* 100 billion +* 1 trillion + +Note: + +- in cerebral cortex humans generally have most neurons, where we have about 20 billion. Even compared to an elephant that has 3 times the number of overall neurons. Though some species of cetaceans (whales and dolphins) approach the number of our cortical neurons and recent research has shown that the long-finned pilot whale likely has more neurons in its cerebral cortex than we do. + +--- + + ## The nervous system and its function is the product of both our genes and our environment
@@ -155,7 +298,7 @@ sinew Note: -* Neuroscience encompasses many fields: genetics, molecular and cell biology, developmental biology, physiology. +* Neuroscience encompasses many fields: genetics, molecular and cell biology, developmental biology, physiology, physics, electrical engineering, computer science. - not nature or nurture, nature and nurture - language, learning to ride a bike @@ -242,136 +385,6 @@ But most single gene mutations do not cause such drastic effects, with a more su --- -## What are brains made of? - -A glob of squishy jello? - -
- -
- -
Wikimedia Commons
- -Cells. (though jello is made of collagen...) - -Note: - -So what are brains made of? Anybody? Jello? What is this 1.5 kg or 3 lb human brain made of? - -Yes it is soft and squishy but it is not just a gelanitous mass like jello. Shown here is a section through a human brain. It is about 20 cm long and if we were to zoom in on a tiny part of it and use a special dye and microscope what we see is that the brain is made of cells. So this is a pyramidal neuron in from the cerebral cortex and its cell body is about 30-40µm in diameter. - ---- - -## Brains are made of cells - -* Camillo Golgi (Italy)– believed that cells in the brain were directly connected forming a **continuous network** (reticular theory). -* Santiago Ramon y Cajal (Spain)– Brains made up of single cells and communicate at specialized areas called synapses. -* Shared Nobel prize in 1906 - -Note: - -Seems fairly obvious now. But wasn't in the 19th c. Cells widely accepted everywhere else in the 1830’s. But neuroscientists were the last to accept this right up until the turn of the 20th c. - -Only after fundamental and rigorous work by these two scientists, C. Golgi and S. Ramon y Cajal in the late 19th c. did we come to appreciate comprised of individual cellular elements rather than a continous network or syncytium. - ---- - -## Golgi staining - -Golgi staining: potassium chromate and silver nitrate (1873) - -
Golgi's drawing of the hippocampus impregnated by his stain
from Golgi's Opera Omnia.
- -
Golgi's drawing of hippocampal dentate gyrus
fig. 9 from Golgi's Nobel lecture
- - -Note: - -Golgi's drawing of hippocampus after performing his black potassum chromate and silver nitrate stain. Bottom is a zoomed in drawing of neurons and their connections in the hippocampal dentage gyrus. - ---- - -## The nervous system is not a syncytium - -* syncytium: a mass of cytoplasm with many nuclei but no internal cell boundries -* reticulum: a fine network or netlike structure -* Camillo Golgi, Nobel Lecture December 11, 1906, *The Neuron Doctrine- theory and facts*: - -
-
- ->"...Far from being able to accept the idea of the individuality and independence of each nerve element, I have never had reason, up to now, to give up the concept which I have always stressed, that nerve cells, instead of working individually, act together, so that we must think that several groups of elements exercise a cumulative effect on the peripheral organs through whole bundles of fibers." - -
- -Note: - -Golgi drew the structure of the hippocampus as being all fused together into a reticulum, no free axon endings - ---- - -## The Neuron Doctrine - -* Santiago Ramon y Cajal -* Neurons are cells. Each is an individual entity anatomically, embryologically, and functionally. -* Neurons have a functional polarity - -
Cajal drawing of golgi stained retina. Cells are separate units and arrows indicate direction of information flow.
- - -Note: - -Neurons in culture have specific endings. EM methods, dye filling experiments. - -Heinrich Wilhelm Gottfried von Waldeyer-Hartz (6 October 1836 – 23 January 1921) was a German anatomist and conceived the word 'neuron'. - -Golgi in his nobel lecture: - ->(3) The neuron is a physiological unit. This fundamental idea which Waldeyer expressed with perfect precision has been enlarged upon both from anatomical and functional sides with additional propositions, for example : **The communication between neurons is only established by casual contact. There is scarcely any nervous tissue apart from the neurons; the neurons are also trophic units.** - ---- - -## The Nobel Prize in Physiology or Medicine 1906 - ->"in recognition of their work on the structure of the nervous system" - -
- -Camillo Golgi -Pavia University -Pavia, Italy - -
- -
- -Santiago Ramón y Cajal -Madrid University -Madrid, Spain - -
- - -Note: - ---- - -## How many neurons in a human brain? - -* 100 thousand -* 10 million -* 100 million -* 1 billion -* 10 billion -* 100 billion -* 1 trillion - -Note: - -- in cerebral cortex humans generally have most neurons, where we have about 20 billion. Even compared to an elephant that has 3 times the number of overall neurons. Though some species of cetaceans (whales and dolphins) approach the number of our cortical neurons and recent research has shown that the long-finned pilot whale likely has more neurons in its cerebral cortex than we do. - ---- - ## Glial cells Glia @@ -591,7 +604,7 @@ Note: Note: -Polarity is everywhere in physics... and biology! +Polarity is everywhere and is everything, in physics... and biology! * electric dipole moments of molecules * earth's magnetic poles @@ -750,7 +763,7 @@ Note: Note: -?Grab Coombs et al., 2006 figures... +todo: need Coombs et al., 2006 figures... --- @@ -787,7 +800,7 @@ Affect vs effect --- -## Neurons communicate by electricity +## Neurons communicate with electrical pulses * Axons project great distances * Use action potentials to transmit information @@ -797,6 +810,8 @@ Affect vs effect Note: +What is electricity? It's energy. It's variance. From the flow of electric charge across a conducting medium. + -- diff --git a/neuroanatomy2.md b/neuroanatomy2.md index c882c13..ff9ec02 100644 --- a/neuroanatomy2.md +++ b/neuroanatomy2.md @@ -3,6 +3,11 @@ * Circuits that do the same kinds of things are grouped into 'systems', e.g. sensory systems and motor systems * Many neurons function between these systems, called associational systems. Associational systems are the most complex and least well characterized systems. +
+2020-10-13T11:43:55-07:00 + +
+ Note: Last time we learned some of the basic cellular anatomy of the nervous system. Today we will put the system in nervous system–– because nervous systems really are greater than the sum of its parts… in other words our brain is not just a blob of cells but it is the interconnections between cells, groups of cells, and brain regions that allow our fantastic feats of emergent biological computation. So lets discuss the overall the structure of the nervous system. @@ -21,9 +26,11 @@ First of all it is a system of systems. In other words… Note: +Left: movie on left illustrates where the central nervous system is in our bodies. + Middle: illustrates the two top level systems of the nervous system, the CNS containing the brain and spinal cord and the PNS containing nerves and ganglia exiting the spinal cord. -Right: outlines the functional hierarchy of different components or systems within the whole nervous system including relations between internal and external environment and sensory receptors in the PNS as well as skeletal muscle and smooth, cardiac muscles that the nervous system controls. +Right: outlines the functional hierarchy of different components or systems within the whole nervous system. This includes relations between the internal and external environment with and sensory receptors in the PNS as well as the relation between skeletal muscle and smooth, cardiac muscles that the nervous system controls. *Don't worry too much about memorizing the exact details of diagrams such as this, focus on the major concepts and their relations* @@ -297,9 +304,9 @@ neural tube/dorsal nerve cord: chordates (fish, amphibians, reptiles, birds, and
-* Dorsal column– sensory signals travels up it to the brain +* Dorsal column– carries sensory signals up to the brain * Lateral columns– also called the cortico-spinal tracts. Carries signals from brain to interneurons and motor neurons in ventral horn -* Ventral columns (sometimes called anterolateral column)– carry pain signals up and motor signals down +* Ventral columns (sometimes called anterolateral column)– carries pain signals up and motor signals down
@@ -313,7 +320,7 @@ Lateral columns-also called the cortico-spinal tracts. Take info from brain and Ventral columns (sometimes called anterolateral column)- carry pain info up and motor info down. -*Cervical enlargement: Gray matter expanded to incorporate more sensory input from limbs and more cell bodies for motor control of limbs* +-Cervical enlargement: Gray matter expanded to incorporate more sensory input from limbs and more cell bodies for motor control of limbs *Rexed's laminae are cytoarchitectonic divisions of spinal cord gray matter, see Table A1* ...don't worry about knowing the lamina @@ -345,7 +352,7 @@ And all information from higher order or more rostral brain structures that goes * Medulla– regulates blood pressure and respiration. * Ventral pons– pontine nuclei, relay signals from cortex to the cerebellum * Dorsal pons– respiration taste and sleep -* Midbrain– auditory and visual systems, substantia nigra pars compacta (dopaminergic neurons). Deteriorates in Parkinson’s disease. +* Midbrain– auditory and visual systems, substantia nigra pars compacta (dopaminergic neurons)
@@ -414,8 +421,12 @@ Note: The tectum of the midbrain, which is latin for ‘roof’ contains the superior and inferior colliculi and is important for processing visual and auditory information as well as shaping motor commands for orienting the head and body. +- red nucleus is part of midbrain, without a corticospinal tract it controls gait. Baby crawling controlled by red nucleus. Arm swinging while walking + Ventral to the cerebral aqueduct through which cerebral spinal fluid circulates, you will find the tegmentum of the midbrain which contains the —> + + -- ## Parkinson’s- loss of dopamine making neurons in the midbrain's substantia nigra @@ -426,6 +437,7 @@ Ventral to the cerebral aqueduct through which cerebral spinal fluid circulates, Note: + substantia nigra pars compacta, a nucleus containing neurons making the neurotransmitter dopamine that are important for regulating motor movements via their connections with the basal ganglia and which are devastated in parkinson’s disease. *dark appearance due to high levels of dark pigment neuromelanin in dopaminergic neurons* @@ -458,7 +470,7 @@ Well here is a grotesque way of convincing you that all you need to live is your * Two hemispheres, several lobes divided by fissures * Neurons in sheets, called cortex * Receives sensory input from spinal cord, motor info from cerebral cortex, balance info from inner ear and vestibular organs -* Primarily used motor control, particularly in making postural adjustments and in fine-tuning movements +* Primarily used for motor control, particularly in making postural adjustments and in fine-tuning movements * Essential for the coordination, planning of movements, learning motor tasks and storing this information
@@ -472,11 +484,14 @@ The cerebellum is located dorsal to the brainstem. It has two… -Neurons are form cortical sheets. +Neurons form cortical sheets like in the cerebral hemispheres. Receives… + +fyi: The MRI image is J. Ackman's brain back in 2009;) + --- ## Cerebellum @@ -556,7 +571,6 @@ Note: The thalamus is located in the middle of the brain… -*red nucleus is part of midbrain, without a corticospinal tract it controls gait. Baby crawling controlled by red nucleus. Arm swinging while walking* -- @@ -617,6 +631,17 @@ Limbic system includes the amygdala, as well as the part of the basal ganglia, p Note: +2500 sq cm in area or about 2.5 sq ft is the human cerebral cortex surface area: +https://academic.oup.com/cercor/article/18/10/2352/384745 + +The little, but very compactly folded cerebellum has 80% of the surface area of cerebral cortex in humans. Compared with monkeys, there is evidence that the cerebellum went through a disproportionaly increased amount of surface area expansion during evolution than even the neocortex. + + +Toro, Roberto; Perron, Michel; Pike, Bruce; Richer, Louis; Veillette, Suzanne; Pausova, Zdenka; Paus, Tomáš (2008-10-01). "Brain Size and Folding of the Human Cerebral Cortex". Cerebral Cortex. 18 (10): 2352–2357. doi:10.1093/cercor/bhm261. ISSN 1047-3211. PMID 18267953. + +Sereno et al. PNAS 2020: +https://doi.org/10.1073/pnas.2002896117 + --- @@ -646,15 +671,19 @@ Note: corpus callosum -: connections the cerebral hemispheres +: connections between the cerebral hemispheres : only in placental mammals (the eutherians) : absent in monotremes and marsupials and other vertebrates (e.g. birds, reptiles, amphibians and fish) -anterior commisure +Other routes for connections between the cerebral hemispheres + +anterior commissure : connects temporal lobes : connects both amygdala : crossed projects from olfactory tracts +hippocampal commissure + --- ## Laminar organization of neocortex @@ -848,7 +877,5 @@ Note:
Neuroscience 5e Fig. A12
-
Pinky and the Brain
- Note: diff --git a/neurophysiology1.md b/neurophysiology1.md index 145a626..a764257 100644 --- a/neurophysiology1.md +++ b/neurophysiology1.md @@ -1,11 +1,12 @@ # Neuronal signaling -* Electrical signals of nerve cells +* Electrical signals of nerve cells * Voltage-dependent membrane permeability * Channels and transporters * Synaptic transmission -* Neurotransmitters, receptors, and their effects -* Molecular signaling within neurons +* Neurotransmitters, receptors, and their effects (second messenger systems, molecular signaling within neurons) + + Note: @@ -14,9 +15,7 @@ So, how do neurons convey information over long distances that results in inform - voltage-dependent membrane permeability - which in turn requires special membrane proteins called ion channels and transporters - synaptic transmission -- which in turn requires neurotransmitters, their membrane bound protein receptors and their resulting effects - -as well as general molecular signaling within neurons as any living cell might have +- which in turn requires neurotransmitters, their membrane bound protein receptors and their resulting effects, including general molecular signaling within neurons as any living cell might have @@ -33,11 +32,11 @@ as well as general molecular signaling within neurons as any living cell might h
-
+
JA, CCO
Note: -To understand the basis of electrical excitability in neurons, we first need to understand that neurons, like other excitable cells, have a difference in electrical potential across the cell membrane when it is at rest. +To understand the basis of electrical excitability in neurons, we first need to understand that neurons, like other living cells, have a difference in electrical potential across the cell membrane when it is at rest. To learn this physiologists stick electrodes inside of cells, including neurons. This electrode is hooked up to a voltmeter and another electrode sits outside the cell as a ground or reference electrode to complete the circuit. The difference in voltage between the inside of the cell and the outside of the cell is monitored over time and displayed on an oscilloscope. @@ -107,7 +106,7 @@ mole electricity : movement of charged carriers through a medium in presence of electric field : duality of electromagnetic waves as wave or particle -: AC (oscillation of electrons in place) vs DC (movment of electrons) +: AC (oscillation of electrons in place) vs DC (movement of electrons) 100 m/s == 360K m/hr == 223 mph @@ -117,8 +116,8 @@ electricity * Can be generated by changing the membrane potential of the neuron * Receptor potentials can be generated from the activation of sensory receptors, from touch, light, sound, and heat -* Synaptic potentials are transmitted from one neuron to another at the synapse -* Action potentials are the booster system to propagate electrical signals a long distance +* Synaptic potentials are generated at the post-synaptic membrane between two neurons +* Action potentials are the high-amplitude, fast timing, regenerative signal that propagate a long distance Note: @@ -151,7 +150,7 @@ To understand the basis of these electrical signals we first need to learn about --- -## Resting membrane potential of neurons +## What is baseline? The resting membrane potential of neurons
@@ -163,7 +162,7 @@ To understand the basis of these electrical signals we first need to learn about
-
+
JA, CC0
@@ -175,12 +174,12 @@ We can think of the cell, a bit like American politics, is polarized with one si This polarization of the cell results in a potential difference across the membrane (remember our water pump example) of about -70 mV -And its there is a concentration gradient in ions (which are charged atoms like sodium, potassium, and chloride) that results in this difference in distribution of charge across the neuron’s membrane +And there is a concentration gradient in ions (which are charged atoms like sodium, potassium, and chloride) that results in this difference in distribution of charge across the neuron’s membrane --- -## Important terms +## Cell membrane potential difference terms * Resting membrane potential– voltage across the cell membrane when it is at rest. Typically –40 to –90 mV * Hyperpolarization– making the membrane potential more negative @@ -191,7 +190,7 @@ Note: Some important terms to know -Just remember that a neuron not eliciting any electrical signals is ‘resting’ at around -70 mV. If electrical current makes the membrane voltage more positive than it is depolarizing. If it is making the membrane more negative than it is hyperpolarizing. Depolarized is less polarized. Hyperpolarized is less polarized. +A neuron not eliciting any electrical signals is "resting" at around -70 mV. If electrical current makes the membrane voltage more positive than it is depolarizing. If it is making the membrane more negative than it is hyperpolarizing. Depolarized is less polarized. Hyperpolarized is more polarized. --- @@ -678,7 +677,7 @@ For a typical neuron at rest, pK : pNa : pCl = 1 : 0.05 : 0.45. Note that becaus --- -## Cells are like this container +## Cells are semi-permeable containers * Semi permeable membranes * Concentration gradients of ions across membranes @@ -690,7 +689,9 @@ For a typical neuron at rest, pK : pNa : pCl = 1 : 0.05 : 0.45. Note that becaus Note: -Cells are a bit like a semipermeable bag of electrolytes with different concentrations of ionic species inside and outside. +Cells are like a semipermeable bag of electrolytes with different concentrations of ionic species inside and outside. + +That is semipermeable containers with some capactity for self-replication --- @@ -721,32 +722,28 @@ Note: Table of physiological relevant intracellular and extracellular ion concentrations in squid neurons and mammalian neurons. Though the values are scaled about 4 times higher in squid, note that K is more concentrated inside, and sodium and chloride are more concentrated outside for both invertebrate and vertebrate neurons. The relevant ratios of different ion species inside and outside are similar. + + --- -## How to test if a neuron is only permeable to K⁺ at rest +## Which ion fluxes are responsible for baseline- the resting potential? -* Need to measure concentrations of ions extracellularly and in the cytoplasm -* Would like to manipulate concentrations of ions outside as well as inside the cell -* Be able to make reliable electrical measurements -* Need an axon big enough to get your electrode in. Initially used the squid giant axon for experiments because they are large (400x larger than a typical mammalian axon). +How to test if a neuron is only permeable to K⁺ at rest? + +* Measure concentrations of ions extracellularly and in the cytoplasm +* Manipulate concentrations of ions outside as well as inside the cell +* Make electrical measurements +* Choose a suitable physiological model + * Need an axon big enough to get your electrode in. + * Use squid giant axon for experiments. large, unmyelinated axons (400x larger than a typical mammalian axon) Note: How do we know the relative permeability of the neuronal membrane at rest or during action potentials? -As I hinted at earlier today and in a previous lecture, the squid giant axon was used to test the basic properties of electrical conduction in neurons in the 1930s to 1950s due to its mm sized diameter. - ---- - -## Squid giant axon - -
Atlantic squid, *Loligo pealei*
- -
Squid giant axon electrophysiology
- - -Note: +Need a physiological model suitable for the available experimental techniques. +The squid giant axon was used to test the basic properties of electrical conduction in neurons in the 1930s to 1950s due to its mm sized diameter. --- @@ -763,7 +760,16 @@ Note: Alan Hodgkin, Andrew Huxley, Bernard Katz +--- +## Squid giant axon + +
Atlantic squid, *Loligo pealei*
+ +
Squid giant axon electrophysiology
+ + +Note: --- @@ -873,14 +879,14 @@ So a summary of the Hodgkin and Katz experiment conclusions... -## Resting membrane and action potentials entail permeabilities to different ions +## Resting membrane and action potentials comprise differing relative permeabilities to different ions
Neuroscience 5e/6e Fig. 2.7
Note: -And as we will soon lecarn, the resting membrane potential and action potential voltage is mostly due to changes in K permeability and Na permeability across the neuronal membrane. As you can see in this figure, the resting membrane potential for a neuron is close to the EK eq potential due to much greater permeability for K. During an action potential Na permeability initially increases, until the Vm approaches the ENa and then Na permeability decreases until the Vm again approaches the resting membrane potential and Pk increases. +And as we will soon learn, the resting membrane potential and action potential voltage is mostly due to relative changes in the permeability of the membrane to and Na vs K across the neuronal membrane. As you can see in this figure, the resting membrane potential for a neuron is close to the EK eq potential due to much greater permeability for K. During an action potential Na permeability initially increases, until the Vm approaches the ENa and then Na permeability decreases until the Vm again approaches the resting membrane potential and Pk increases. --- diff --git a/neurophysiology2.md b/neurophysiology2.md index 9e9e529..83f12b9 100644 --- a/neurophysiology2.md +++ b/neurophysiology2.md @@ -12,6 +12,10 @@
Neuroscience 5e Fig. 2.7
+
+ +
+ Note: We learned last time that the experiments of Hodgkin, Huxley, and Katz showed that the Vm during an AP approaches ENa. And they thought that this might be due to changes in permeability for Na in the cell membrane that changes during the course of an action potential. Thus Hodgkin and Huxley hypothesized that APs can be explained by ion channels that change their permeability due to voltage— that these channels are voltage-gated. @@ -290,18 +294,18 @@ TTX and TEA experiments from Moore 1967 J Gen Physiol; Armstrong and Binstock, 1 * Another way of describing permeability is using membrane conductance (*g*). Conductance (measured in siemens, *S*) is the reciprocal of resistance * *g = 1/R* -* Ohm’s law: +* Ohm’s law: * *I = V/R* * *I = gV* * For an ion *x*, * *Ix* = ionic current flow, *Ex* = equilibrium potential * The membrane potential (*Vm*) minus the equilibrium potential (*Ex*) is the electrochemical driving force acting on an ion, thus *V = Vm - Ex* * *Ix = gxV* - * *Ix = gx(Vm - Ex)* -* Solve for *g*: - * *gx = Ix/(Vm - Ex)* -* *Ix* determined from measurement of current changes plus or minus ion (or during pharmacological inhibition) -* *Ex* calculated from Nernst equation using concentrations of inside and outside ions + * *Ix = gx(Vm - Ex)* +* Solve for *g*: + * *gx = Ix/(Vm - Ex)* +* *Ix* determined from measurement of current changes plus or minus ion (or during pharmacological inhibition) +* *Ex* calculated from Nernst equation using concentrations of inside and outside ions
@@ -393,7 +397,7 @@ Can also see increases in K conductance during the AP, but this K+ conductance ( Note: -The threshold is a point of criticality in the system like trying to balance on a knifes edge. Just imagine any self-organized phenomena in nature: a snow field suddenly turning into an avalanche, liquid water turning into gas or solid forms, videos of cats or korean pop stars suddenly going viral. The point at which the states of these systems veer on the edge of order or disorder is the point of criticality also known to physicists as a phase transition. +The threshold is a point of criticality in the system like trying to balance on a knifes edge. Just imagine any self-organized phenomena in nature: a snow field suddenly turning into an avalanche, liquid water turning into gas or solid forms, videos of cat memes suddenly going viral. The point at which the states of these systems veer on the edge of order or disorder is the point of criticality also known to physicists as a phase transition. --- @@ -548,6 +552,31 @@ figure comparing action potential propagation speed in an unmyelinated and myeli action potential genaration occurs only at specific points, the nodes of Ranvier, along the myelinated axon +-- + +## Multiple sclerosis + +* Disease caused by myelination defects and loss of neurons +* Seems like an autoimmune disease +* 1/750 of population in US get multiple sclerosis (MS) +* 1/40 risk if a parent has it +* 1/3 if an identical twin gets it +* Genetic and environmental risk factors + +Note: + +onset between ages 20-40. + +blindness, motor weakness, paralysis. + +ultimate cause of MS remains unclear. Immune system contributes to damage and is key component. Immune cells in CSF and injection of myelin in animals can cause EAE. Autoimmune disorder. Or persistent infection with a human retrovirus? + + +* women to men ratio 3/2 +* Genetic component is likely the effect of multiple genes + + + --- ## The Nobel Prize in Physiology or Medicine (1963) @@ -587,25 +616,3 @@ Note: ---- - -## Multiple sclerosis - -* Disease caused by myelination defects and loss of neurons -* Seems like an autoimmune disease -* 1/750 of population in US get multiple sclerosis (MS) -* 1/40 risk if a parent has it -* 1/3 if an identical twin gets it -* Genetic and environmental risk factors - -Note: - -onset between ages 20-40. - -blindness, motor weakness, paralysis. - -ultimate cause of MS remains unclear. Immune system contributes to damage and is key component. Immune cells in CSF and injection of myelin in animals can cause EAE. Autoimmune disorder. Or persistent infection with a human retrovirus? - - -* women to men ratio 3/2 -* Genetic component is likely the effect of multiple genes diff --git a/neurophysiology3.md b/neurophysiology3.md index e711cee..38bd933 100644 --- a/neurophysiology3.md +++ b/neurophysiology3.md @@ -7,6 +7,10 @@ * Problem– Voltage clamping cannot look at individual channels...it's measuring the aggregate current flowing through a whole bunch of channels at once. What does an individual channel look like? How does it work? * Solution– Patch Clamping +
+ +
+ Note: Today we will take a closer look at the nature of **ion channels** and how they are able to exhibit their remarkable properties that enable action potentials and all forms of electrical signaling in the nervous system. @@ -514,7 +518,7 @@ K | 0.27 | 0.46
-
+
JA, [CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)
Note: diff --git a/neurophysiology4.md b/neurophysiology4.md index e6aeb87..096f468 100644 --- a/neurophysiology4.md +++ b/neurophysiology4.md @@ -337,8 +337,6 @@ Note: Criteria depicted here -[https://www.quora.com/How-many-types-of-neurotransmitters-are-there-in-a-human-brain](https://www.quora.com/How-many-types-of-neurotransmitters-are-there-in-a-human-brain) - It depends on how you count, but maybe 30 - 100 different molecule types, with 10 of them doing 99% of the work. More than 100 different neurotransmitters have been identified. There are two main broad categories of neurotransmitters: "Small molecule" neurotransmitters (glutamate, GABA, acetylcholine, biogenic amines (dopamine, serotonin, noradrenaline, and histamine)) and neuropeptides (opioid peptides, substance P). ATP/purines and unsaturated fatty acids like endocannabinoids (anandamide, 2-AG) also can act as neurotransmitters. @@ -737,15 +735,6 @@ Tetanus toxin and various types of botulinum toxin act by preventing exocytosis. Note: -NSF -: NEM-sensitive fusion protein (orig found to be important for fusion of vesicles with membranes of Golgi apparatus) -: ATPase - -SNAPs -: soluble NSF attachment proteins - -SNARES -: 'SNAP receptors' diff --git a/neurotransmitters1.md b/neurotransmitters1.md index 4f9d80b..e835df1 100644 --- a/neurotransmitters1.md +++ b/neurotransmitters1.md @@ -1,952 +1,519 @@ -## Neurotransmitters +## Neurotransmitter receptors -* More than 100 different molecules -* Two main types– - * small molecule neurotransmitters - - acetylcholine, amino acids, monoamines, purines - * peptide neurotransmitters - - polypeptides, 3–36 amino acids in length and often derived from longer polypeptides +
+
+ +* Neurotransmitter receptors are embedded in the plasma membrane of the post-synaptic cell and are always one of the following: + 1. ion channels (**ionotropic** or 'ligand-gated' ion channel) + 2. receptors that interface with separate ion channels (**metabotropic**, or G-protein coupled receptors) +* Neurotransmitter receptor activation following ligand (neurotransmitter) binding results in the opening of ion channels and ionic flux. This ion flux is the postsynaptic current (or 'end plate' current for a muscle cell) +* These postsynaptic currents result in depolarization or hyperpolarization of the membrane potential (postsynaptic potential or 'end plate' potential) depending on the **types of ions** flowing through the channel pores and the ions' respective **electro-chemical driving forces** + +
Note: -We already defined what a neurotransmitter is. It is a substance that must be present inside a presynaptic neuron, it’s release must be dependent on calcium flux from an AP, and it must have specific receptors on the postsynaptic neuron. +Diving a bit deeper into the structure and function of neurotransmitter (NT) receptors now... -Abnormalities of neurotransmitter function contributes to wide range of neurological diseases and psychiatric disorders +For synaptic transmission, NT receps are generally located in the post-synaptic membrane (*though there are exceptions, e.g. some transmitter receptors may be located on pre-synaptic membrane or at non synaptic site in the cell*). -two types: very small molecule and big molecule neurotransmitters. +Two classes of NT receptors. + +In either case, NT binding will result in ion channels opening and ion flux across the post-synaptic membrane. Whether this results in hyperpolarization or depolarization of the membrane will be due to the types of ions flowing through the channels and their respective electrical/chemical driving forces (Nernst) + +Changing the postsynaptic membrane potential inturn affects the **electrochemical** driving forces regulating ion flux. So currents may change amplitude and direction during the course of a postsynaptic potential. Read on... --- -## Small-molecule neurotransmitters +## Ionotropic neurotransmitter receptors + +* Neurotransmitter binds receptor +* Channel opens, allowing ions to flow through + +
Neuroscience 5e Fig. 5.3
+
Neuroscience 5e Fig. 5.16
+ + +Note: + +The ionotropic receptors are the ones you’ve probably seen in our synaptic diagrams so far, where NT binds directly to an ion channel pore, causing it to open and allow ions to move through the pore. + +* neurotransmitter binds +* channel opens +* ions flow across membrane + + +--- + +## Metabotropic neurotransmitter receptors + +* G-protein coupled receptor signalling results in modulation of nearby ion channels for metabotropic receptors. + +
Neuroscience 5e fig. 5.16 | Neuroscience 6e fig. 7.4
+ + +Note: + +Metabotropic transmitter receptors are G-protein coupled receptors, also known as seven-transmembrane domain receptors in you cell biology courses. + +* neurotransmitter binds +* g protein binds and is activated +* g protein subunits or intracellular messengers modulate ion channels +* ion channel opens +* ions flow across membrane + +Effector enzymes for activated G-proteins include: + +* Gs: --> adenylyl cyclase --> ATP--> cAMP --> PKA --> incr prot phosphor +* Gq: phopholipase C --> [DAG --> PKC; IP3 --> Ca^2+^] --> incr prot phosphor, Ca binding proteins +* Gi: --< adenylyl cyclase --< cAMP --< PKA --> decr prot phosphor +* Or guanylyl cyclase (GTP->cGMP) --> Protein kinase G etc. +* All G-protein receptor activations lead to downstream second messsaging (cAMP, diacylglycerol, IP3) --> protein kinases, Ca2+ --> leading to phosphorylation state changes including... ion channels +* Three amplification steps here! (receptor production of G proteins, adenylyl cyclase production of cAMP, protein kinase substrate phosphorylation). Source signal amplification. + +* 3% of our genome is codes for protein phosphorlation state genes (500 protein kinases and 200 protein phosphatases) + * cAMP dependent protein kinases (PKA) + * Ca^2+^ - calmodulin depedent protein kinase type II (CaMKII predominant in neurons, most abundant protein component of the post synaptic density) + * Protein kinase C (PKC)- activated by Ca^2+ (moves PKC from cytosol to membrane) and diacylglycerol (DAG) and then phosphorylates substrates + + + +-- + +## Neurotransmitter receptors video summary + +
Neuroscience 5e Animation 5.3
+ +Note: + +--- + +## Nicotinic acetylcholine receptors (nAChR) + +* Ionotropic receptor +* Acetylcholine (ACh) binds the nAChR– this opens the channel +* ACh causes nAChR to open *transiently* and *stochastically* (patch clamp studies) +* An action potential causes lots of ACh molecules to be released simultaneously, transiently opening many nACh receptors +* The summed current flow into the muscle cell is called the end plate current (EPC). Current flow changes the transmembrane potential of the muscle, the end plate potential (EPP), which triggers an action potential + +Note: + +So to understand the properties of ionotropic neurotransmitter receptors lets start with the nicotinic ACh receptor (abbreviated nAChR). + +nACh Receptors are ionotropic or ligand-gated receptors where the ligand is ACh and are the receptor you’ve heard the most thus far, being the one that underlies end plate currents at the neuromuscular junction that cause end plate potentials in muscle cells. + +stochastic +: having a random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely + + +--- + +## Patch clamping shows ACh gated currents through nicotinic ACh receptors
-
acetylcholine
Neuroscience 5e Fig. 6.1
-
purines
Neuroscience 5e Fig. 6.1
-
-
amino acids
Neuroscience 5e Fig. 6.1
-
biogenic amines (monoamines)
Neuroscience 5e Fig. 6.1
- - -Note: - -Not expected to know chemical formulas for any neurotransmitters - -*Most of which share a hydroxylated benzene ring* -*Catechol, also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula C6H4(OH)2* - ---- - -## Peptide neurotransmitters - -
peptides
methionine enkephalin: an endogenous opioid peptide; Neuroscience 5e Fig. 6.1
- -Note: - -- also called neuropeptides - -- usually 3-30 amino acids long -- more than 100 peptides - - ---- - -## Neurotransmitter synthesis - -
-
- -* Synthesis can occur - * at the soma (neuropeptides) - * at synaptic terminals (small molecule transmitters) -* Vesicle packaging– requires specific transporters on vesicle membrane. There are small clear-core vesicles (ACh and amino acids) and large dense-core (neuropeptides). Biogenic amines can be in either vesicle type. - -
- -Note: - -Small molecules are generated from biosynthetic enzymes - -Neuropeptides are generated by translation followed by post-translational processing - -*Biogenic amines present in either type of vesicle* - -What about unconventional neurotransmitters such as ATP, NO, endocannabinoids? What type of packaging for release if any? - - - -small clear-core vesicles -: clear centers in EM -: 40–60 nm diameter - -large dense-core vesicles -: electron dense centers -: 90–250 nm diameter - --- - -## Synaptic vesicle types - -
small clear-core vesicles
Neuroscience 5e Fig. 5.5
-
large dense-core vesicles
Neuroscience 5e Fig. 5.5
- -Note: - -Neurons often make both a conventional small molecule neurotransmitter (such as glutamate, GABA or dopamine) together with one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the small molecule neurotransmitters in small synaptic vesicles. - -The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal swellings (varicosities) and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations. - -This refers to the larger amount of material inside the dense-core vesicles, which contain not only neurotransmitters, but also proteases and other peptide chains that have been cleaved from the active neurotransmitter. Greater electron scattering in EM. - -Chemical fixation -: for biological specimens fixation aims to stabilize the specimen's macromolecular structure by chemical crosslinking of proteins with aldehydes such as formaldehyde and glutaraldehyde and lipids with osmium tetroxide. - ---- - -## Small molecule transmitters are synthesized at the presynaptic terminal - -
-
- -Enzymes produced in nerve cell body are transported down axon. Neurotransmitter is synthesized and packaged at synaptic terminal. - -
- -
Neuroscience 5e Fig. 5.5
- - -Note: - -* synthesis of enzymes in cell body -* slow (0.5–5.0 mm/day) axonal transport of enzymes -* synthesis and packaging of transmitter in local synaptic terminal -* breakdown of transmitter by enzymes in extracellular space or nearby astrocytes, transport of precursors back into synaptic terminal - ---- - -## Peptide transmitters are synthesized in the cell body - -
-
- -Neuropeptides are synthesized in the nerve cell body, loaded into vesicles, and transported down the axon via microtubules. - -
- -
Neuroscience 5e Fig. 5.5
- - -Note: - -* synthesis of propeptide precursors and enzymes in cell body -* fast axonal transport (400 mm/day) of enzymes and peptide precursors inside vesicles down microtubules (requires ATP motor proteins like kinesin) -* proteolytic processing of propeptides by enzymes to produce peptide neurotransmitter -* peptide neurotransmitter diffuses away, degraded by proteolytic enzymes (typically on extracellular surface) - ---- - -## Large dense-core vesicles release after high frequency stimulation - -
Neuroscience 5e Fig. 5.12
- -Note: - -* release of small molecule transmitters inside clear core vesicles -* release of both types of neurotransmitter - -TODO: -* experimental evidence -* spatial location of release - - -Release– small clear-core vesicles release fast, large dense-core vesicles take more effort. Location in synapses is different - ---- - - -## Small molecule neurotransmitters - -
-
- -* Acetylcholine -* Amino acids - * glutamate - * aspartate - * GABA - * glycine -* Monoamines - * dopamine - * norepinephrine - * epinephrine - * serotonin - * histamine -* Purines (ATP) - -
- -Note: - ---- - -## Acetylcholine - -* The neurotransmitter used at the neuromuscular junction. Also used at synapses in visceral motor system and at some CNS synapses– called cholinergic neurons -* Synthesized from acetyl CoA and choline by choline acetyl transferase (ChAT)– its presence is a good indication that the neuron is cholinergic -* Removed from synapse by acetylcholine esterase (AChE) which has high activity– can cleave 5000 molecules per second -* Sarin "nerve gas" is a AChE inhibitor - -Note: - -ACh: skeletal muscle excitation vs release from vagus nerve that slows down heart beat (cardiac muscle)— - -* Ligand gated channel that depolarizes skeletal muscle fibers vs g-protein coupled receptor that results in hyperpolarization of cardiomyocytes. - -Typical enzyme rates may be 1000 substrates molecules per second. AChE thought to be one of the fastest enzymes in the body. - -choline -: a water soluable essential nutrient -: quaternary ammonium salt -: present in plant and animal tissues -: choline is part of phophatidylcholine and sphingolipids (sphingomyelin in myelin) phospholipids on cell membranes -: also acetylcholine precursor - - -ACh discovery and WWI history timeline - ---- - -## Acetylcholine synthesis - -
-
Neuroscience 5e Fig. 6.2
- -Note: - -from krebs cycle you get Acetyl CoA. Na-Choline cotransporter exchanges Na ions for choline. - -choline acetyltransferase... - -VAChT packs ACh into vesicles using the acidic vesicle's proton gradient. The gradient is established through active transport by the standard vacuolar H+-ATPase (V-ATPase), a highly conserved enzyme to convert ATP hydrolysis energy to proton transport across membranes. - - --- - -## AChE Inhibition - -
-
- -* Sarin and Soman: toxic irreversible AChE inhibitors. Also known as “nerve gases” for use in chemical warfare -* Designed to dispersed as a vapor cloud or spray, which allows their entry into the body through skin contact or inhalation. Drug quickly penetrates into bloodstream and is distributed to all organs, including the brain -* Symptoms: profuse sweating and salivating, uncontrollable vomiting, gasping for breath, convulsing, and gruesome death. These are due to rapid accumulation of ACh and overstimulation of cholinergic synapses throughout the CNS and PNS. Death occurs through asphyxiation due to paralysis of the muscles of the diaphragm - -
- -
Psychopharmacology Chp. 6, 2006 Sinauer
- - -Note: - -parasympathetic (Ach) vs sympathetic (norep) - --- - -## Acetylcholine synthesis video summary - -
Neuroscience 5e Animation 6.1
- -Note: - - ---- - -## Small molecule neurotransmitters - -
-
- -* Acetylcholine -* Amino acids - * glutamate - * aspartate - * GABA - * glycine -* Monoamines - * dopamine - * norepinephrine - * epinephrine - * serotonin - * histamine -* Purines (ATP) - -
- -Note: - - ---- - -## Glutamate - -* Most abundant neurotransmitter -* Nearly all excitatory neurons in the CNS are glutamatergic -* Does not cross the blood brain barrier -* Glutamine is most common precursor, glutaminase converts it to glutamate -* Retrieved from synapse by glutamate transporters in glia and neurons. Astrocytes turn glutamate to glutamine and spit it back out -* Too much glutamate can kill the post-synaptic neuron (excitotoxicity). A major problem after damage due to stroke - -Note: - -Most common neurotransmitter for normal brain function. Almost all excitatory neurons in CNS are glutamatergic. Half of all synapses estimated to use this transmitter. - -Glutamate (glutamic acid) is non-essential a.a. (meaning non-essential per dietary requirements) that does not cross the blood brain barrier. Synthesized inside neurons by local precursors. - -*Essential amino acids are: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine* - -*Monosodium glutamate (MSG, also known as sodium glutamate) is the sodium salt of glutamic acid* - ---- - -## Glutamate synthesis - -
-
- -* synthesized from **glutamine** by **glutaminase** -* packaged into vesicles by vesicular glutamate transporters (**VGLUT**) using proton gradient setup by V-ATPase -* removed from cleft by excitatory amino acid transporter **EAAT** -* converted into glutamine by glutamine synthetase in the glial cell -* tranported back to neuron via system N transporter 1 (**SN1**) and system A transporter 2 (**SAT2**) - - -
- -
Neuroscience 5e Fig. 6.5
- - -Note: - -Metabolized into glutamate by mitochondrial enzyme glutaminase. Also glucose metabolism from Krebs cycle can also produce glutamate. - -Packaged into vesicles by vesicular glutamate transporters (VGLUT). 3 different VGLUTs identified. - -Removed from cleft by excitatory a.a. transporters (EAATs). These are family of 5 Na⁺ dependent glutamate cotransporters. Some in glial cells, some in presynaptic terminals. - -Glutamate in glial cells by EAAT converted into glutamine by enzyme glutamine synthetase. - -Glutamine then transported out by different transporter system N transporter 1 (SN1) then back into nerve cells by system A transporter 2 (SAT2). - - - - --- - -## Glutamate synthesis video summary - -
Neuroscience 5e Animation 6.2
- -Note: - -ACh role in Alzheimers: basal forebrain innervation to neocortex vs hippocampus. Cholinergic neuron degradation vs local postsynaptic neuron effects… - ---- - -## GABA and glycine - -* Inhibitory neurons primarily use GABA or glycine -* Activation of GABA or glycine receptors typically reduces probability of firing action potentials -* GABA (gamma-aminobutyric acid)– made from glutamate by glutamic acid decarboxylase (GAD) - * GAD requires Vitamin B6 as cofactor -* Glycine– about 1/2 of neurons in spinal cord use glycine -* Hyperglycinemia– defect in glycine uptake and removal leading to severe mental retardation - -Note: - -As many as a third of synapses in the brain use GABA as an inhibitory transmitter. Most commonly found in local circuit neurons. - -glycine encephalopathy: - -from [http://ghr.nlm.nih.gov/condition/glycine-encephalopathy](http://ghr.nlm.nih.gov/condition/glycine-encephalopathy): - ->Glycine encephalopathy, which is also known as nonketotic hyperglycinemia or NKH, is a genetic disorder characterized by abnormally high levels of a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body. A lack of this enzyme allows excess glycine to build up in tissues and organs, particularly the brain, leading to serious medical problems. - --- - -## Glycine - -* Inhibitory neurotransmitter -* Makes the post-synaptic membrane more permeable to Cl⁻. Can result in hyperpolarization of the post-synaptic cell -* Glycine receptor is primarily found in the ventral spinal cord -* Strychnine - * glycine receptor antagonist which can bind to the receptor without opening the Cl⁻ channel (i.e. it inhibits inhibition) - * spinal hyperexcitability - -
*Strychnos nux-vomica*
- -Note: - -Strychnine -: highly toxic, colorless, bitter crystalline alkaloid -: from *Strychnos nux-vomica* native to India, Sri Lanka, and Indonesia - ---- - -## GABA synthesis - -
-
- -* synthesized from glutamate by glutamic acid decarboxylase (**GAD**) -* transported into vesicles by vesicular inhibitory amino acid transporter (**VIAAT**), using proton gradient setup by V-ATPase. -* Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called **GATs** - -
- -
Neuroscience 5e Fig. 6.8
- -Note: - -synthesized from glutamate by glutamic acid decarboxylase (**GAD**) - -transported into vesicles by vesicular inhibitory amino acid transporter (**VIAAT**), using proton gradient setup by V-ATPase. - -Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called **GATs** - --- - -## Glycine synthesis - -
Neuroscience 5e Fig. 6.8
- -Note: - -Synthesized from glucose by serine hydroxy-methlytransferase (**GAD**) - -Transported into vesicles by vesicular inhibitory amino acid transporter (**VIAAT**), using proton gradient setup by V-ATPase. - -Removal by neurons and glia by Na⁺ dependent glycin cotransporters **GATs** - - -Taurine and beta-alanine (other amino acids) can act as agonists for glycine receptors and also gaba receptors to some degree [Mori:2002] - - -[Mori:2002]: Mori M., Gahwiler B. H. and Gerber U. (2002) Beta-alanine and taurine as endogenous agonists at glycine receptors in rat hippocampus in vitro. J. Physiol. 539, 191–200 - ---- - -## Small molecule neurotransmitters - -
-
- -* Acetylcholine -* Amino acids - * glutamate - * aspartate - * GABA - * glycine -* Monoamines - * dopamine - * norepinephrine - * epinephrine - * serotonin - * histamine -* Purines (ATP) - -
- -Note: - ---- - -## Monoamine neurotransmitters (biogenic amines) - -* Catecholamines– dopamine, norepinephrine, and epinephrine - * All derived from tyrosine. Tyrosine hydroxylase is the rate limiting step and is a good histological marker for catecholaminergic neurons -* Histamine -* Serotonin -* Are implicated in many complex behaviors - -Note: - - -**Monoamines** (a subset of biogenic amines. Biogenic amines are monoamines + trace amines like like tryptamine, phenethylamine, melatonin) regulate many functions in the CNS and PNS. Ranging from homeostatic functions to cognition and attention. - -* All come from same synthesis pathway -* defects in function implicated in many psychiatric disorders -* targets of many drugs of abuse - -*Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group.* - -- *reserpine used as antipsychotic, depletes Norep at synaptic terminals by blocking vesicle loading* -- *organic structure template: R—NH2* - --- - -## Catecholamine synthesis - -
Neuroscience 5e Fig. 6.10
- - -Note: - ---- - -## Dopamine - -* Produced by the enzyme DOPA decarboxylase -* Made by substantia nigra pars compacta (which connects to corpus striatum for coordination of body movements) -* Does not cross the blood brain barrier, but levadopa (L-DOPA) does -* Parkinson’s treatments include L-DOPA plus degradation enzyme inhibitors -* Cocaine works by inhibiting the dopamine cotransporter DAT - -Note: - -Synthesized in cytoplasm of presynaptic terminals. - -Loaded into synaptic vesicles by vesicular monoamine transporter (VMAT). Dopamine in synaptic cleft is terminated by reuptake of dopamine into nerve terminals or glia cells by a Na-dependent dopamine cotransporter called DAT. Cocaine works by inhibiting DAT, increasing dopamine concentrations in synaptic cleft. - -Amphetamine also inhibits DAT as well as a transporter for norepinephrine - -* Catabolized by monoamine oxidase and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT. Inhibitors of these enzymes are targets of some kinds of antidepressants (phenelzine and tranylcypromine) -* Acts throught GPCRs. D3 parallels that of other metabotropic receptors like mAChR. Subtypes act by activating or inhibiting adenylyl cyclase. -* Activation leads to complex behaviors. Antagonists can cause catalepsy (state where difficult to initiate voluntary movement). -* L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. -* it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase. - -*Parkinson's treatment: LDOPA + enzyme inhibitors info* -*blood brain barrier info* - -*Encephalitis lethargica, sleeping sickness, 40 yrs later Oliver Sacks in NYC treats them with L-DOPA* - -* neostriatum -* Part of - * Basal ganglia - * Reward system -* Components - * Ventral striatum - * Dorsal striatum - -The corpus striatum, a macrostructure which contains the striatum, is composed of the entire striatum and the globus pallidus. The lenticular nucleus refers to the putamen together with the globus pallidus. - - - - ---- - -## Projections from dopaminergic neurons in the human brainstem - -
Neuroscience 5e Fig. 6.11
- - -Note: - - --- - -## Dopamine synthesis video summary - -
Neuroscience 5e Animation 6.3
- -Note: - - ---- - -## Norepinephrine - -* also called noradrenaline -* Comes from dopamine by way of dopamine-β-hydroxylase -* Sympathetic ganglion cells use it– project to visceral motor system (fight or flight response) -* Used as a transmitter from locus coeruleus in brainstem (rostral pons)– projects to areas that are involved in sleep, attention, and feeding -* Its reuptake mechanism, the norepinephrine transporter (NET), is a target of amphetamines - -Note: - -VMAT for loading into vesicles - -Norep transporter (NET) is a Na⁺ depedent cotranporter. NET is a target of amphetamines. - -alpha and beta adrengergic receptors. GPCRs. Some alphas lead to slow depolarization. Some lead to slow hyperpolarization (acting on different K⁺ channels). - -norepinephrine also released into blood by adrenal medulla of adrenal gland - -locus coeruleus -: input– hypothalamus, cingulate cortex, amygdala, cerebellum, raphe nuclei -: output– everywhere, spinal cord, brainstem, cerebellum, hypothalamus, thalamus, amygdala, cerebral cortex -: activation mediates an excitatory effect, giving rise to arousal/wakefulness - - ---- - -## Projections from noradrenergic neurons in the human brainstem - -
Neuroscience 5e Fig. 6.11
- - -Note: - - --- - -## Norepinephrine synthesis video summary - -
Neuroscience 5e Animation 6.4
- -Note: - - - -* Epinephrine/Adrenaline– present at lower levels than the others -* Epinephrine made by neurons in rostral medulla. Project to thalamus and hypothalamus - ---- - -## Epinephrine - -* Adrenaline– present at lower levels than the others -* Made by neurons in rostral medulla. Project to thalamus and hypothalamus - --- - -## Projections from adrenergic neurons in the human brainstem - -
Neuroscience 5e Fig. 6.11
- - - ---- - -## Serotonin - -* 5-hydroxytryptamine (5-HT) -* Made from tryptophan -* Reuptake by specific serotonin transporters -* Many antidepressants act by inhibiting serotonin reuptake (selective serotonin reuptake inhibitors-SSRIs; e.g. Prozac, Zoloft) -* Found primarily in groups of neurons in the raphe region of the pons and upper brainstem -* The raphe nucleus projects widespread in forebrain areas that are implicated in sleep and wakefulness and mood - - -Note: - -* dorsal raphe and median raphe nuclei. In brain stem. raphe nuclei just ventral to the 4th ventricle stretching from medulla -* vesiclular monoamine transporter **VMAT** loads this (as well as other monoamines) into synaptic vesicles. - -turkey/tryptophan—> sleep? Yes— but not really ([http://www.snopes.com/food/ingredient/turkey.asp](http://www.snopes.com/food/ingredient/turkey.asp)), you’d have to eat a lot more (maybe 3x more) than at a particular meal. And furthermore, lots of protein sources include amounts of tryptophan similar to or greater than that of turkey per gram of food content (including eggs, fish, cheese, and some nuts, seeds, legumes). Tryptophan is present in all proteins, but is also - -And besides well timed carbohydrate ingestion with/after tryptophan consumption is important for increasing tryptophan transport from blood vessels and into brain tissue: - -[http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2](http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2): - ->The small, all-carbohydrate snack is tryptophan's ticket across the blood-brain barrier, where it can boost serotonin levels. - -Tryptophan competes with other large aromatic neutrally charged amino acids for passage into brain from blood vessels. But tryptophan is the only amino acid known to bind non-covalently with serum albumin (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1133271/?page=1) (Curzon, 1973; Smith and Pogson, 1980). This is thought to protect it from insulin induced cellular metabolism (insulin rising after eating carbohydrates of course) by bringing tryptophan to high enough concentrations in blood to favor entry into brain. Indicates that the timing of carbohydrate ingestion may be helpful. - -Study looking at food/protein composition type and quantitative mesaures of cerebral serotonin levels after consumption (5-HT levels can change 8-fold in rat): https://doi.org/10.1016/j.physbeh.2009.05.004 - - - ---- - - -## Histamine - -* Made from histidine, a metabolite of monoamine oxidase -* Released by neurons in hypothalamus (tuberomammilary nucleus) that send projections to all parts of the brain and spinal cord -* Mediates arousal and attention -* Histamine receptors are in the immune system and in the CNS. Sedative effects of diphenhydramine (Benadryl) act through the CNS - - -Note: - -* synthesized from histidine by - -* H1 receptors (antagonists used for treating motion sickness because role in vestibular function) -* H2 receptors control secretion of gastric acid in digestive system - -*transported into vesicle by VMAT as catecholamines* - - -diphenhydramine -: benadryl -: inhibits H1 receptors -: also has some serotonin reuptake inhibitor capability -: also has some anticholinergic (muscarinic) capability - ---- - -## Projections from serotonergic and histaminergic neurons - -These projections are sparse (low synapse density) but widespread (most brain regions). - -
-
histaminergic axons from tuberomamillary nucleus of hypothalamus, -serotonergic axons from dorsal raphe nucleus of brain stem +
Patch clamp recording of current through single nAChR. +Channels open for varying amounts of time while ACh is bound.
-
Neuroscience 6e Fig. 6.17, 5e Fig. 6.13
+
Neuroscience 5e Fig. 5.17
+
+ + +Note: + +The binding of a neurotransmitter to its receptor usually opens (*sometimes closes*) ion channels. + +The figure shows a simple case. In the absence of ACh, the nAChR is closed. In the presence of high [ACh] (the channel always has ACh bound), the channel opens and closes. These repeated brief openings are seen as downward deflections corresponding to inward current. Notice the current amplitudes in this patch clamp trace below are unitary or quantal indicating that a single channel is being recorded in this case... + +These look like microscopic currents you get in single channel patch clamp recordings like we discussed previously. + +If this piece of membrane and channel is from a muscle cell than a bunch of these currents put together are the ones that give rise to the end plate potentials we for muscle cells before. + + +--- + +## Activation of nAChR at neuromuscular synapses + +
end plate currents in a voltage-clamped muscle cell
Neuroscience 5e Fig. 5.17
+ +
+
+depolarizing end plate potential recorded +in muscle cell due to the inward end plate currents +
Neuroscience 5e Fig. 5.17
+ +Note: + +Imagine we are doing an experiment where we stimulate a motor neuron and we record end plate currents in a muscle cell... + +...then the traces on the left show inward currents through these ionotropic ACh channels in the muscle cell, showing the currents stemming from a single channel, 10 channels, and hundreds of thousands of channels. Notice the amplitudes of the currents scale. + +...and the panel on the right shows postsynaptic potential change or end plate potential produced by the EPC as we discussed previously + +As we will learn shortly, the channel opened by ACh lets mostly Na⁺ through resulting in these inward currents that depolarize the muscle cell, resulting in EPPs and typically resulting in APs as we’ve discussed before. + +[from http://www.ncbi.nlm.nih.gov/books/NBK21586/](http://www.ncbi.nlm.nih.gov/books/NBK21586/): + +>Two factors greatly assisted in the characterization of the nicotinic acetylcholine receptor. First, this receptor can be rather easily purified from the electric organs of electric eels and electric rays; these organs are derived from stacks of muscle cells (minus the contractile proteins) and thus are richly endowed with this receptor. (In contrast, this receptor constitutes a minute fraction of the total membrane protein in most nerve and muscle tissues.) Second, α-bungarotoxin, a neurotoxin present in snake venom, binds specifically and irreversibly to nicotinic acetylcholine receptors. + +* acetylcholine causes opening of a cation channel in the receptor capable of transmitting 15,000 – 30,000 Na⁺ or K⁺ ions a millisecond + + + +--- + +## What ions flow through the nicotinic ACh receptor? + +
+
+ +* Nernst equation– the equilibrium potential of a cell for ion *x* is the potential at which the electrochemical driving forces is balanced for ion *x* (i.e there is no net flow of ion *x* at the equilibrium potential *Ex*) + * Thus if one measured the ACh dependent current flow at different potentials, one could determine the membrane potential (*Vm*) where there is no net ion flux (*Ix* = 0). This is called the **reversal potential** or *Erev* +* The end plate current (EPC) at the muscle cell must therefore be *IACh* and is equal to the driving force on an ion multiplied by its permeability (remember Ohm's law: *I = gV*) +* *IACh = gACh(Vm – Erev)* +* Predicts that current will be inward at potentials more negative than *Erev*, becomes small at potentials approaching *Erev*, and then becomes outward at potentials more positive then *Erev* + +
+ +Note: + +Now using our good friend the Nernst eqn, which you can recall is… + +Since we know there isn’t any net flow of an ion x, at the Ex, we can measure the ACh dependent currents at different potentials and figure out the potentials at which current flow is 0. + +When we are talking about the potential at which postsynaptic currents like the endplate current reverses from inward net ion flux to outward net ion flux, we call this potential the reversal potential denoted Erev. + +We can call the endplate current then the IAch or the current flowing through the ACh receptor at skeletal muscle endplate membrane and IAch is therefore equal to the driving force (which is the difference between Vm and Erev) multiplied by the permeability for ACh gAch. + +This would then predict that current will be inward at potentials more negative than Erev… + +* Predicts that current will be negative (inward) at potentials more negative than Erev, becomes small at potentials approaching Erev, and becomes positive (outward) at potentials more positive then Erev. + +--- + +## Measure postsynaptic (end plate) currents while stimulating motor neuron + +
voltage-clamping a postsynaptic muscle fiber
Neuroscience 5e Fig. 5.18
+ + +Note: + +A postsynaptic muscle fiber is voltage clamped to control the muscle fiber’s membrane potential, while the presynaptic neuron is stimulated to cause ACh release at the end plate synapse. + + +--- + +## Hypothetical ion channel selectivities and the reversal potential + +
Current-voltage relationships for different ion selectivities
Neuroscience 2e 2001
+ + +Note: + +So let’s imaging what the current-voltage relationships would look like for different channel selectivities. Remember the reversal potential is when there there is no net ion flux, so it 0 nA on all these graphs and if a channel is selective to only K, it would be equal to the Ek. + +If the channel was selective only to Na, than the Erev would be equal to ENa. Same for chloride. + +If the channel was a non-selective cation channel (passing both K and Na) then the current-voltage relationship would look like... + +11Na, 12Mg, 17Cl, 19K, 20Ca + + +*Ca2+ ions flow through CaV channels at a rate of ~106 ions s−1, but Na+ conductance is 500fold less through CaV channels* [#Tang:2014] +*extracellular [Na+] is nearly 70fold higher than Ca2+, thus Ca2+ selectivity is crucial* [#Tang:2014] +*Ca2+ and Na+ have nearly identical diameters (~2 Å)* 1 Å = 100 pm (Ca2+ larger atomic size, but Na+ has larger ionic size|hydration shell). +*Ca2+ selectivity is from high affinity binding, preventing Na+ permeability. Multi site pore, with knock on mechanism to push Ca2+ ions through* [#Tang:2014] + +[#Tang:2014]: Tang, L., Gamal El-Din, T. M., Payandeh, J., Martinez, G. Q., Heard, T. M., Scheuer, T., Zheng, N., and Catterall, W. A. (2014). Structural basis for Ca2+ selectivity of a voltage-gated calcium channel, Nature, 505(7481), 56-61. PMID 24270805 + + +--- + +## Postsynaptic Vm affects the magnitude and direction of end plate currents + +
+
+Effect of Vm on postsynaptic muscle fiber end plate currents. +Inward current is down, outward current is up. +*Notice the current reverses at 0 mV* +
+
Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960
+ + +Note: + +These little transients are just stimulus artifacts, but look at the postsynaptic end plate currents in these at these different Vms. Look what happens when Vm is at 0mV, there is no current and then above 0 mV it flips from being inward to net outward current... + +We already know that ACh is essential for the end plate currents-- therefore we can say that this EPC is IAch. Therefore what is the Erev for IAch? + + +--- + +## Postsynaptic Vm affects the magnitude and direction of end plate currents + +
Expected Erev if nAChR permeable only to K⁺, Cl⁻, or Na⁺
Neuroscience 5e Fig. 5.18
+
Observed Erev is in between Ek and ENa
Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960
+ +Note: + +[#Takeuchi:1960]: Takeuchi, A. and Takeuchi, N. (1960). On the permeability of end-plate membrane during the action of transmitter, J Physiol, 154(), 52-67. PMID 13774972 + +--- + +## Shifting ENa+ or EK+ shifts Erev of the neuromuscular endplate current + +
Neuroscience 5e, Fig. 5.19, Takeuchi J Physiol 1960
+ + +Note: + +So it seems that the ACh activated ion channels are equally permeable to Na and K and this was tested in 1960 by Akira and Noriko Takeuchi by changing the extracellular concentration of these ions. As predicted, lowering [Na] shifts Erev to the left and and raising the external [K] shifts Erev to the right. + +--- + +## What ions flow through the nACh receptor? + +
+
+ +* Voltage clamping experiments show that there are large inward currents at -110 mV, smaller currents at -60 mV and no current at 0 mV. Outward currents at +70 mV. Therefore Erev = 0 +* Erev is not at any of the equilibrium potentials for a single ion, lies in between K⁺ (-100 mV) and Na⁺ (+70 mV) +* Altering the K⁺ concentration or the Na⁺ concentration will change the membrane potential. Therefore both Na⁺ and K⁺ are permeable through the nACh receptor +* nACh receptor can conduct both Na⁺ and K⁺ ions. The direction of flow is dependent on the membrane potential. The normal resting state of muscle is -100 mV, well below 0 mV (Erev) therefore normally at rest Na⁺ rushes in with very little K⁺ rushing out + +
+ +Note: + +As we will see in a minute voltage clamp experiments show that there is a… + +Erev… + +Furthermore, altering… + +Therefore we can conclude that the nAChR can conduct both Na and K ions. + +--- + + +## Na⁺ and K⁺ movements during EPCs and EPPs + +
Neuroscience 5e Fig. 5.20
+ +Note: + +Even though these ionotropic channels opened by ACh are permeable to both Na and K, at the resting membrane potential the EPC is generated primarily by Na influx because of the reduced driving force on K since at Vrest the membrane potential is closer to Ek. + +In fact the Na⁺ and K⁺ permeabilities of the nAChR channel are similar, therefore the **magnitudes of the Na⁺ and K⁺ currents depends on the driving forces present for each ion** -- +## Na⁺ and K⁺ movements during EPCs and EPPs -## Synthesis of histamine and serotonin +
EPC: inward or outward; EPP: depolarizing or hyperpolarizing
Neuroscience 5e Fig. 5.20
-
Neuroscience 5e Fig. 6.14
+Note: + +Here is the key: you get inward currents at potentials more negative the Erev and you get outward currents at potentials more positive than Erev. + +The resulting EPPs depolarize postsynaptic cell at potentials more negative than Erev and potentials more positive than Erev hyperpolarize the cell. + +*Since the Na⁺ and K⁺ permeabilities of this channel are similar, the magnitudes of the Na⁺ and K⁺ currents depends on the driving forces present for each ion* + + + +--- + +## nAChR summary + +* When the nAChR opens at normal resting potentials many Na⁺ ions rush in and a few K⁺ rush out. This causes a depolarizing EPP in the muscle cell. As the Vm during the EPP approaches Erev, outward K⁺ flux is equal to inward Na⁺ flux. Therefore if the nACh receptor is open long enough, it will drive Vm to Erev. +* If Erev is above action potential threshold, the probability of an action potential occurring is increased +* If Erev is below action potential threshold, the probability of an action potential occurring decreased + +Note: + +[http://www.nature.com/nrd/journal/v1/n6/full/nrd821.html: ](http://www.nature.com/nrd/journal/v1/n6/full/nrd821.html) + +>In the case of this modified muscle nAChR, the conductance of the pore is sensitive to the presence of negative charge at three locations that form three negatively charged rings in and near the M2 domain56. So, intensive studies of the M2 segment have been carried out to determine the amino acids that are responsible for the cationic or anionic selectivity of receptors. + +--- + +## Similar mechanisms exist at all chemical synapses + +For synapses between neurons: + +* Postsynaptic current (PSC) is similar to an end plate current +* Post synaptic potential (PSP) is similar to an end plate potential + * Excitatory PSP (EPSP)– increases likelihood of an action potential occurring + * Inhibitory PSP (IPSP)– decreases likelihood of an action potential occurring + +Note: + +So now let's generalize the properties that we’ve learned about EPCs through ionotropic AChR and their effects on EPPs at the neuromuscular junction to the case of chemical synapses between any pair of neurons... + +But instead of the so called EPPs, we'll call the postsynaptic potentials between neurons we call excitatory PSP if it increases the likelihood of an AP firing in a postsynaptic cell and inhibitory PSP if it decr the probability of an AP occurring in a postsynaptic cell. + + + + + +--- + +## EPSP summation + +* Unlike the neuromuscular junction– at synapses between neurons an individual EPSP is usually not very strong, typically well below threshold. +* Multiple EPSPs need to be summed together for the neuron's Vm to reach threshold. Individual neurons can receive thousands synapses. It's the summation of EPSPs and IPSPs that determine whether or not an action potential occurs. Note: --- -## Peptide neurotransmitters +## Excitatory postsynaptic potential (EPSP) -* 3-36 or so amino acids, cleaved from larger precursor proteins -* Catabolized by peptidases -* 5 general classes, brain/gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing hormones, all others -* Packaged into large dense-core vesicles -* Generally used as co-transmitters + + +
EPSP mediated by glutamate activating nonselective cation channels
Neuroscience 5e Fig. 5.21
Note: -* Many peptides known to be hormones also act as neurotransmitters -* melanocyte-stimulating hormone, adrenocorticotropin, Beta-endorphin regulate complex responses to stress -* substance P and opioid peptides involved in the perception of pain +Imagine an experiment like the endplate potental recordings at the neuromuscular junction before but this time on a neuron in the CNS --- +--- -## Amino acid sequences of peptide neurotransmitters +## Inhibitory postsynaptic potential (IPSP) type 1 -
Neuroscience 5e fig. 6.17
+
+
+ +* An IPSP mediated by a GABA activated chloride selective channel that hyperpolarizes the neuron +* Reversal potential for the Cl⁻ current is negative to the resting potential and action potential threshold + +
+ +
IPSP mediated by Cl⁻ selective ion channel
Neuroscience 5e Fig. 5.21
Note: --- -## Synthesis of neuropeptides +## IPSP type 2 -* Neuropeptides are synthesized as pre-propeptides in the nerve cell bodies -* This includes a signal sequence that targets the peptides to the inside of the endoplasmic reticulum -* The signal sequence is cleaved to form the propeptide +* The reversal potential for the Cl⁻ current is positive to the resting potential but negative to threshold +* Activation of Cl⁻ channels depolarizes the neuron. Stabilizes membrane potential below threshold + +
IPSP mediated by Cl⁻ selective ion channel
Neuroscience 5e Fig. 5.21
+
EPSP: Erev > thresh, IPSP: Erev< thresh
Neuroscience 5e Fig. 5.21
+ + +Note: + +Imagine if a separate EPSP input brought Vm of this neuron to -41 mV, just below -40mV threshold. Since this is now postive to the ECl of -50mV, further activity at the IPSP synapses will now hyperpolarize the neuron back towards -50mV. + +This can also be called shunting inhibition. In this case Na⁺ channels could persistently be in a state of inactivation due to small ongoing depolarizing and hyperpolarzing pulses keeping the neurons Vm below threshold. + +So just remember, the key is that if the Erev for the neurotransmitter receptor is more positive than threshold than it is excitatory. If it is more negative than threshold than it is inhibitory. + +>Blocking NKCC1 with bumetanide disrupts excitatory synapse development in the cortex + +*Bumetanide, a selective NKCC1 inhibitor, has been demonstrated to suppress certain forms of epileptiform activity in vitro and in vivo, presumably by attenuating the depolarizing effect of GABA (Dzhala et al., 2005; Kilb et al., 2007)* + +>effect of GABA on membrane polarity depends on the Cl gradient created by the expression of Na -K -2Cl cotransporter (NKCC) and K-Cl cotransporter (KCC). NKCC1 imports Cl and is expressed from the embryonic stage until the first postnatal week, whereas KCC2 exports Cl and is weakly expressed at birth and upregulated as the brain matures (Plotkin et al., 1997; Rivera et al., 1999; Li et al., 2002). The temporal expression patterns of these two transporters correspond to the switch of GABA from being excitatory to inhibitory during the first few weeks of rodent postnatal life (Delpire, 2000). + +--- + +## Summation of postsynaptic potentials + +
Neuroscience 5e Fig. 5.22
+
Neuroscience 5e Fig. 5.22
+ +Note: + + + +--- + +## Summation + +* In general EPSPs in neurons are small 0.2–0.4 mV +* Most neurons are somewhere between 10–20 mV below threshold. If everything was linear that it would take the sum of 50 or so inputs to trigger AP +* Not so simple-- synaptic inputs can be summed in space and time within a neuron +* Recall a single neuron may have as many as 10,000 different synapses. Some are excitatory some inhibitory, some strong some weak. Some at the tips of dendrites, some near the cell body +* Integration of all these little postsynaptic bioelectric waves determines whether the neuron fires an action potential Note: --- -## Synthesis of neuropeptides +--- -
Neuroscience 5e Fig. 6.16
+## Neural integration + +
+
+ +* How does a neuron integrate all the information it is getting? +* In many neurons the decision to initiate an action potential is at the axon hillock. Contains a high density of voltage dependent Na^+^ channels and is contains membrane with lowest threshold +* Axon hillock is senses the local state of the cell, which is the combination of all the EPSPs and IPSPs going on at one time +* This is due graded potentials that spread passively +* Temporal summation, process by which consecutive synaptic potentials at the same site are added together. +* Spatial structure of the determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches + +
Note: -Proteolytic processing of the pre-propeptides, pre-proopiomelanocortin and pre-proenkaphalin +* Different synapses will have different time constants +* Some dendrites have voltage gated Na^+^ channels (albeit lower density than axons), these can amplify inputs +* Length constant of the cell determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches -Processing the polypeptides that make the final neuropeptdies happens in an neurons cell body. Propeptide packaged into vesicles in golgi network. Final peptide processing occurs after packaging into vesicles. Multiple neuroactive peptides can be released from a single vesicle. +Time constant +: time needed for for resistive current (I~r~, current due to ions flowing through channels) and membrane potential (V~m~) to reach **63%** of their *asymptotic values* is proportional to the combination of resistance and capacitance of the circuit in question (across the cell membrane) +: membrane current (I~m~) is sum of I~r~ and the capacitive current (I~c~) +: I~m~ = I~r~ + I~c~ +: capacitance of membrane: during change in applied voltage or current across membrane, positively charged ions pile on surface of one side of membrane and **electrostatically** interact with cations on the other side of membrane surface (membrane acts as thin impermeable surfaces in parallel, like a capacitor), repeling them and inducing immediate, fast capacitive current along membrane +: capacitive current falls with an exponential time course. And the membrane potential rises with **same exponential** time course +: Relation of membrane potential at time *t* during charging of capacitance is given by V~t~ = V~inf~(1 - *e*^-t/RC^), where V~inf~ is the membrane potential at an infinite asymptotic value of the exponential curve. When t = RC, then we have V~t~ = V~inf~ ( 1 - *e*^-1^) ==> V~inf~ (0.63) -proopiomelanocortin -: precursor for melanocyte-stimulating hormone, adrenocorticotropin, beta-endorphin -: regulate complex responses to stress and modulation of pain -: beta-endorphin binds to mu-opioid receptors +```javascript +console.log( 1 - Math.E ** -1) +``` -ACTH -: adrenocorticotropic hormone -: corticotropin -: secreted by anterior pituitary gland -: produced in response to stress -: increases production of cortisol in adrenal glands + + +--- + +## Summation of postsynaptic potentials video + +
Neuroscience 5e Animation 5.2
+ - ---- - -## Examples of peptide transmitters– Opioids - -* Bind to same post-synaptic receptors as opium -* Family with more than 20 members, three basic groups: endorphins, enkephalins, and dynorphins -* Often co-localized with GABA and serotonin -* Tend to act as depressants, used for analgesics -* Repeated use often leads to tolerance and addiction - -Note: - -Opioids are named because they bind to same postsynaptic receptors as opium. - -* opium poppy cultivated for 5000 yrs -* opium contains a variety of plant alkaloids, predominantly morphine. Morpheus, greek god of dreams. Very effective analgesic. Fentanyl, synthetic opiate with 80 times analgesic potency of morphine - -Opioid peptides distributed throughout the brain. Colocalize with GABA and 5-HT. Tend to be depressants. They act like analgesics when injected intracerebrally. Initiate effects through GPCRs. Activate at low concentrations (nM to uM). mu, delta, kappa opioid receptor subtypes play role in reward and addiction. mu-receptor is primary site for opiate drugs. - -TODO: opiate drug info - -Naloxone is a non-selective and competitive opioid receptor antagonist. - --- - -## Examples of peptide transmitters– Substance P - -* Substance P– 16 amino acid peptide -* Present in human hippocampus, neocortex, and GI tract (hence a brain-gut peptide) -* Involved in the perception of pain -* Released from C-fibers which carry information about pain and temperature - -Note: - -accidental discovery of substance P. Ominous sounding compound from Area 51? No. It was an unidentified component of powder extracts from brain and intestine. High conc. in hippocampus, neocortex, and GI tract. A brain/gut peptide. Release of Subst P in cfibers can be inhibited by spinal interneurons releasing opioid peptides. - - - - ---- - -## Unconventional neurotransmitters– cannabinoids - -
-
- -* Cannabinoids - * Endocannabinoids - * anandamide - * 2-arachidonylglycerol (2-AG) - * Δ9-tetrahydrocannabinol (THC) - * main psychoactive compound in *cannabis sativa*/*indica* -* Bind to G-protein coupled receptors (GPCRs): CB1 & CB2 -* CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum - -
- -
-
Anandamide
-
2-AG
-
THC
-
- - -Note: - -Unconventional neurotransmitters. Released from neurons, regulated by Ca²⁺, and have specific receptors, but not released from synapses by exocytotic vesicle mechanisms. Often unconventional NTs are associated with retrograde signaling from post to pre. - -These endocannabinoids are actually unsaturated fatty acids from enzymatic digestion of membrane lipids. Production stimulated by second messengers within postsynaptic neuron, typically a rise in postsynaptic Ca²⁺ concentration. - -Ohno-Shosaku *Neuron* 2001: endocannabinoids act on cannabinoid receptors (CB1) to reduce GABA release from presynaptic inhibitory neurons. Inhibiting inhibition (disinhibition). - --anandamide --2-arachidonylglycerol (2-AG) - -[Anandamide](https://en.wikipedia.org/wiki/Anandamide) -: N-arachidonoylethanolamine -: essential fatty acid neurotransmitter -: derived from non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid, an essential ω-6 polyunsaturated fatty acid) -: effects can occur in either CNS or PNS -: effects by CB1 cannabinoid receptors in the CNS and CB2 cannabinoid receptors in the PNS [#Pacher:2006] -: CB2 receptors involved in regulating immune system function -: found in chocolate [#Tomaso:1996] -: endocannabinoids, long chain fatty acids like anandamide found in drosophila melanogaster [#Jeffries:2014] but cannabinoid receptors are not [#McPartland:2001] - -[#Pacher:2006]: Pacher, P., Bátkai, S., and Kunos, G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy, Pharmacol Rev, 58(3), 389-462 - -[#Tomaso:1996]: di Tomaso, E., Beltramo, M., and Piomelli, D. (1996). Brain cannabinoids in chocolate, Nature, 382(6593), 677-8 - -[#Jeffries:2014]: Jeffries, K. A., Dempsey, D. R., Behari, A. L., Anderson, R. L., and Merkler, D. J. (2014). Drosophila melanogaster as a model system to study long-chain fatty acid amide metabolism, FEBS Lett, 588(9), 1596-602 - -[#McPartland:2001]: McPartland, J., Di Marzo, V., De Petrocellis, L., Mercer, A., and Glass, M. (2001). Cannabinoid receptors are absent in insects, J Comp Neurol, 436(4), 423-9 - -Mechanism of release not clear, but likely that these hydrophobic signals diffuse through the postsynaptic membrane to reach cannabinoid receptors on nearby cells. Action terminated by carrier mediated transport into postsynaptic neuron and hydrolyzed by enzyme fatty acid amide hydrolase (FAAH). - -Psychotropic -: psychoactive -: chemical substance that changes brain function resulting in altered perception, mood, or conciousness - -* cannabis sativa | cannabis indica - * used for hemp (fiber, oil, seed) - * phytocannabinoids (85 active identified in cannabis) - -THC: -* agonist of both CB1 and CB2 -* mild to moderate analgesic effects (dorsal root ganglion and PAG), antiemetic (anti-nausea) -* tolerance appears to be irregular throughout mouse brain areas -* possesses mild antioxidant activity -* Bioavailability 10–35% (inhalation), 6–20% (oral)[3] -* Protein binding 97–99%[3][4][5] -* Metabolism Mostly hepatic by CYP2C[3] -* Biological half-life 1.6–59 h,[3] 25–36 h (orally administered dronabinol) -* Excretion 65–80% (feces), 20–35% (urine) as acid metabolites[3] - -cannabidiol: a major phytocannabinoid, accounting for up to 40% of the plant's extract. More complex effects than THC, may potentiate effects through CB1 density increases, inhibition of FAAH. Allosteric modulator of mu-opioid receptors. Less understood. - -cannabinol: higher affinity for CB2 (but weaker than THC). Breakdown product of THC - --rimonabant, synthetic drug - -GPCRs: - -CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum - -CB2 expressed in cells throughout the immune system. T cells, macrophages, B cells, peripheral nerve terminals (relief of pain), microglial cells - -major CB2 targets are: >immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kupffer cells in the liver, etc. - ->multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).[25] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.[#Demuth:2006] - -inhibits inhibition on presynaptic GABAergic neurons. Inhibits IPSCs. disinhibitory effect. - -[#Demuth:2006]: Demuth DG, Molleman A (2006). "Cannabinoid signalling". Life Sci. 78 (6): 549–63. doi:10.1016/j.lfs.2005.05.055. PMID 16109430. - -Other cannabinoid-like compounds found in other plants (e.g. Echinacea). Some like b-caryophyllene (volatile plant terpene) are quite common among plants (incl cannabis sativa) and act as agonist (nM concentrations) of CB2 [#Gertsch:2010]. Most of these that have been found so far have affinities for CB2. Mostly just THC with non-selective affinity for CB1 (and CB2 modulation) at nM concentrations so far. But Falcarinol also has non-selective CB1 affinity (at µM concentrations) [#Gertsch:2010], and is widespread in Apiaceae (celery, carrot, parsley family) like *Daucus carota* also in red ginseng *Panax ginseng*) though it might work as an inverse agonist. - -[#Gertsch:2010]: Gertsch, J., Pertwee, R. G., and Di Marzo, V. (2010). Phytocannabinoids beyond the Cannabis plant - do they exist?, Br J Pharmacol, 160(3), 523-9 - -*Apiaceae* -: angelica, anise, arracacha, asafoetida, caraway, carrot, celery, Centella asiatica, chervil, cicely, coriander (cilantro), culantro, cumin, dill, fennel, hemlock, lovage, cow parsley, parsley, parsnip, cow parsnip, sea holly, giant hogweed and silphium - -*Daucus carota* -: wild carrot -: 'Queen Anne's lace' -: domesticated carrots are cultivars of a subspecies - --- - -## CB1 receptors are expressed widely throughout the forebrain - -
CB1 expression in rodent
Neuroscience 5e Box 6. M. Herkenham, NIMH
- - - -Note: - -TODO: -* human expression evidence -* human rodent brain comparison - ---- - -## Summary - -
Neuroscience 5e Table 6.1
diff --git a/neurotransmitters2.md b/neurotransmitters2.md index e835df1..4f9d80b 100644 --- a/neurotransmitters2.md +++ b/neurotransmitters2.md @@ -1,519 +1,952 @@ -## Neurotransmitter receptors +## Neurotransmitters -
+* More than 100 different molecules +* Two main types– + * small molecule neurotransmitters + - acetylcholine, amino acids, monoamines, purines + * peptide neurotransmitters + - polypeptides, 3–36 amino acids in length and often derived from longer polypeptides + +Note: + +We already defined what a neurotransmitter is. It is a substance that must be present inside a presynaptic neuron, it’s release must be dependent on calcium flux from an AP, and it must have specific receptors on the postsynaptic neuron. + +Abnormalities of neurotransmitter function contributes to wide range of neurological diseases and psychiatric disorders + +two types: very small molecule and big molecule neurotransmitters. + +--- + +## Small-molecule neurotransmitters + +
+
acetylcholine
Neuroscience 5e Fig. 6.1
+
purines
Neuroscience 5e Fig. 6.1
+
+
amino acids
Neuroscience 5e Fig. 6.1
+
biogenic amines (monoamines)
Neuroscience 5e Fig. 6.1
+ + +Note: + +Not expected to know chemical formulas for any neurotransmitters + +*Most of which share a hydroxylated benzene ring* +*Catechol, also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula C6H4(OH)2* + +--- + +## Peptide neurotransmitters + +
peptides
methionine enkephalin: an endogenous opioid peptide; Neuroscience 5e Fig. 6.1
+ +Note: + +- also called neuropeptides + +- usually 3-30 amino acids long +- more than 100 peptides + + +--- + +## Neurotransmitter synthesis + +
-* Neurotransmitter receptors are embedded in the plasma membrane of the post-synaptic cell and are always one of the following: - 1. ion channels (**ionotropic** or 'ligand-gated' ion channel) - 2. receptors that interface with separate ion channels (**metabotropic**, or G-protein coupled receptors) -* Neurotransmitter receptor activation following ligand (neurotransmitter) binding results in the opening of ion channels and ionic flux. This ion flux is the postsynaptic current (or 'end plate' current for a muscle cell) -* These postsynaptic currents result in depolarization or hyperpolarization of the membrane potential (postsynaptic potential or 'end plate' potential) depending on the **types of ions** flowing through the channel pores and the ions' respective **electro-chemical driving forces** +* Synthesis can occur + * at the soma (neuropeptides) + * at synaptic terminals (small molecule transmitters) +* Vesicle packaging– requires specific transporters on vesicle membrane. There are small clear-core vesicles (ACh and amino acids) and large dense-core (neuropeptides). Biogenic amines can be in either vesicle type.
Note: -Diving a bit deeper into the structure and function of neurotransmitter (NT) receptors now... +Small molecules are generated from biosynthetic enzymes -For synaptic transmission, NT receps are generally located in the post-synaptic membrane (*though there are exceptions, e.g. some transmitter receptors may be located on pre-synaptic membrane or at non synaptic site in the cell*). +Neuropeptides are generated by translation followed by post-translational processing -Two classes of NT receptors. +*Biogenic amines present in either type of vesicle* -In either case, NT binding will result in ion channels opening and ion flux across the post-synaptic membrane. Whether this results in hyperpolarization or depolarization of the membrane will be due to the types of ions flowing through the channels and their respective electrical/chemical driving forces (Nernst) +What about unconventional neurotransmitters such as ATP, NO, endocannabinoids? What type of packaging for release if any? -Changing the postsynaptic membrane potential inturn affects the **electrochemical** driving forces regulating ion flux. So currents may change amplitude and direction during the course of a postsynaptic potential. Read on... - ---- - -## Ionotropic neurotransmitter receptors - -* Neurotransmitter binds receptor -* Channel opens, allowing ions to flow through - -
Neuroscience 5e Fig. 5.3
-
Neuroscience 5e Fig. 5.16
- - -Note: - -The ionotropic receptors are the ones you’ve probably seen in our synaptic diagrams so far, where NT binds directly to an ion channel pore, causing it to open and allow ions to move through the pore. - -* neurotransmitter binds -* channel opens -* ions flow across membrane - - ---- - -## Metabotropic neurotransmitter receptors - -* G-protein coupled receptor signalling results in modulation of nearby ion channels for metabotropic receptors. - -
Neuroscience 5e fig. 5.16 | Neuroscience 6e fig. 7.4
- - -Note: - -Metabotropic transmitter receptors are G-protein coupled receptors, also known as seven-transmembrane domain receptors in you cell biology courses. - -* neurotransmitter binds -* g protein binds and is activated -* g protein subunits or intracellular messengers modulate ion channels -* ion channel opens -* ions flow across membrane - -Effector enzymes for activated G-proteins include: - -* Gs: --> adenylyl cyclase --> ATP--> cAMP --> PKA --> incr prot phosphor -* Gq: phopholipase C --> [DAG --> PKC; IP3 --> Ca^2+^] --> incr prot phosphor, Ca binding proteins -* Gi: --< adenylyl cyclase --< cAMP --< PKA --> decr prot phosphor -* Or guanylyl cyclase (GTP->cGMP) --> Protein kinase G etc. -* All G-protein receptor activations lead to downstream second messsaging (cAMP, diacylglycerol, IP3) --> protein kinases, Ca2+ --> leading to phosphorylation state changes including... ion channels -* Three amplification steps here! (receptor production of G proteins, adenylyl cyclase production of cAMP, protein kinase substrate phosphorylation). Source signal amplification. - -* 3% of our genome is codes for protein phosphorlation state genes (500 protein kinases and 200 protein phosphatases) - * cAMP dependent protein kinases (PKA) - * Ca^2+^ - calmodulin depedent protein kinase type II (CaMKII predominant in neurons, most abundant protein component of the post synaptic density) - * Protein kinase C (PKC)- activated by Ca^2+ (moves PKC from cytosol to membrane) and diacylglycerol (DAG) and then phosphorylates substrates + +small clear-core vesicles +: clear centers in EM +: 40–60 nm diameter +large dense-core vesicles +: electron dense centers +: 90–250 nm diameter -- -## Neurotransmitter receptors video summary +## Synaptic vesicle types -
Neuroscience 5e Animation 5.3
+
small clear-core vesicles
Neuroscience 5e Fig. 5.5
+
large dense-core vesicles
Neuroscience 5e Fig. 5.5
Note: ---- +Neurons often make both a conventional small molecule neurotransmitter (such as glutamate, GABA or dopamine) together with one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the small molecule neurotransmitters in small synaptic vesicles. -## Nicotinic acetylcholine receptors (nAChR) +The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal swellings (varicosities) and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations. -* Ionotropic receptor -* Acetylcholine (ACh) binds the nAChR– this opens the channel -* ACh causes nAChR to open *transiently* and *stochastically* (patch clamp studies) -* An action potential causes lots of ACh molecules to be released simultaneously, transiently opening many nACh receptors -* The summed current flow into the muscle cell is called the end plate current (EPC). Current flow changes the transmembrane potential of the muscle, the end plate potential (EPP), which triggers an action potential - -Note: - -So to understand the properties of ionotropic neurotransmitter receptors lets start with the nicotinic ACh receptor (abbreviated nAChR). - -nACh Receptors are ionotropic or ligand-gated receptors where the ligand is ACh and are the receptor you’ve heard the most thus far, being the one that underlies end plate currents at the neuromuscular junction that cause end plate potentials in muscle cells. - -stochastic -: having a random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely +This refers to the larger amount of material inside the dense-core vesicles, which contain not only neurotransmitters, but also proteases and other peptide chains that have been cleaved from the active neurotransmitter. Greater electron scattering in EM. +Chemical fixation +: for biological specimens fixation aims to stabilize the specimen's macromolecular structure by chemical crosslinking of proteins with aldehydes such as formaldehyde and glutaraldehyde and lipids with osmium tetroxide. --- -## Patch clamping shows ACh gated currents through nicotinic ACh receptors +## Small molecule transmitters are synthesized at the presynaptic terminal -
-
Patch clamp recording of current through single nAChR. -Channels open for varying amounts of time while ACh is bound. -
-
Neuroscience 5e Fig. 5.17
-
- - -Note: - -The binding of a neurotransmitter to its receptor usually opens (*sometimes closes*) ion channels. - -The figure shows a simple case. In the absence of ACh, the nAChR is closed. In the presence of high [ACh] (the channel always has ACh bound), the channel opens and closes. These repeated brief openings are seen as downward deflections corresponding to inward current. Notice the current amplitudes in this patch clamp trace below are unitary or quantal indicating that a single channel is being recorded in this case... - -These look like microscopic currents you get in single channel patch clamp recordings like we discussed previously. - -If this piece of membrane and channel is from a muscle cell than a bunch of these currents put together are the ones that give rise to the end plate potentials we for muscle cells before. - - ---- - -## Activation of nAChR at neuromuscular synapses - -
end plate currents in a voltage-clamped muscle cell
Neuroscience 5e Fig. 5.17
- -
-
-depolarizing end plate potential recorded -in muscle cell due to the inward end plate currents -
Neuroscience 5e Fig. 5.17
- -Note: - -Imagine we are doing an experiment where we stimulate a motor neuron and we record end plate currents in a muscle cell... - -...then the traces on the left show inward currents through these ionotropic ACh channels in the muscle cell, showing the currents stemming from a single channel, 10 channels, and hundreds of thousands of channels. Notice the amplitudes of the currents scale. - -...and the panel on the right shows postsynaptic potential change or end plate potential produced by the EPC as we discussed previously - -As we will learn shortly, the channel opened by ACh lets mostly Na⁺ through resulting in these inward currents that depolarize the muscle cell, resulting in EPPs and typically resulting in APs as we’ve discussed before. - -[from http://www.ncbi.nlm.nih.gov/books/NBK21586/](http://www.ncbi.nlm.nih.gov/books/NBK21586/): - ->Two factors greatly assisted in the characterization of the nicotinic acetylcholine receptor. First, this receptor can be rather easily purified from the electric organs of electric eels and electric rays; these organs are derived from stacks of muscle cells (minus the contractile proteins) and thus are richly endowed with this receptor. (In contrast, this receptor constitutes a minute fraction of the total membrane protein in most nerve and muscle tissues.) Second, α-bungarotoxin, a neurotoxin present in snake venom, binds specifically and irreversibly to nicotinic acetylcholine receptors. - -* acetylcholine causes opening of a cation channel in the receptor capable of transmitting 15,000 – 30,000 Na⁺ or K⁺ ions a millisecond - - - ---- - -## What ions flow through the nicotinic ACh receptor? - -
+
-* Nernst equation– the equilibrium potential of a cell for ion *x* is the potential at which the electrochemical driving forces is balanced for ion *x* (i.e there is no net flow of ion *x* at the equilibrium potential *Ex*) - * Thus if one measured the ACh dependent current flow at different potentials, one could determine the membrane potential (*Vm*) where there is no net ion flux (*Ix* = 0). This is called the **reversal potential** or *Erev* -* The end plate current (EPC) at the muscle cell must therefore be *IACh* and is equal to the driving force on an ion multiplied by its permeability (remember Ohm's law: *I = gV*) -* *IACh = gACh(Vm – Erev)* -* Predicts that current will be inward at potentials more negative than *Erev*, becomes small at potentials approaching *Erev*, and then becomes outward at potentials more positive then *Erev* +Enzymes produced in nerve cell body are transported down axon. Neurotransmitter is synthesized and packaged at synaptic terminal. + +
+ +
Neuroscience 5e Fig. 5.5
+ + +Note: + +* synthesis of enzymes in cell body +* slow (0.5–5.0 mm/day) axonal transport of enzymes +* synthesis and packaging of transmitter in local synaptic terminal +* breakdown of transmitter by enzymes in extracellular space or nearby astrocytes, transport of precursors back into synaptic terminal + +--- + +## Peptide transmitters are synthesized in the cell body + +
+
+ +Neuropeptides are synthesized in the nerve cell body, loaded into vesicles, and transported down the axon via microtubules. + +
+ +
Neuroscience 5e Fig. 5.5
+ + +Note: + +* synthesis of propeptide precursors and enzymes in cell body +* fast axonal transport (400 mm/day) of enzymes and peptide precursors inside vesicles down microtubules (requires ATP motor proteins like kinesin) +* proteolytic processing of propeptides by enzymes to produce peptide neurotransmitter +* peptide neurotransmitter diffuses away, degraded by proteolytic enzymes (typically on extracellular surface) + +--- + +## Large dense-core vesicles release after high frequency stimulation + +
Neuroscience 5e Fig. 5.12
+ +Note: + +* release of small molecule transmitters inside clear core vesicles +* release of both types of neurotransmitter + +TODO: +* experimental evidence +* spatial location of release + + +Release– small clear-core vesicles release fast, large dense-core vesicles take more effort. Location in synapses is different + +--- + + +## Small molecule neurotransmitters + +
+
+ +* Acetylcholine +* Amino acids + * glutamate + * aspartate + * GABA + * glycine +* Monoamines + * dopamine + * norepinephrine + * epinephrine + * serotonin + * histamine +* Purines (ATP)
Note: -Now using our good friend the Nernst eqn, which you can recall is… - -Since we know there isn’t any net flow of an ion x, at the Ex, we can measure the ACh dependent currents at different potentials and figure out the potentials at which current flow is 0. - -When we are talking about the potential at which postsynaptic currents like the endplate current reverses from inward net ion flux to outward net ion flux, we call this potential the reversal potential denoted Erev. - -We can call the endplate current then the IAch or the current flowing through the ACh receptor at skeletal muscle endplate membrane and IAch is therefore equal to the driving force (which is the difference between Vm and Erev) multiplied by the permeability for ACh gAch. - -This would then predict that current will be inward at potentials more negative than Erev… - -* Predicts that current will be negative (inward) at potentials more negative than Erev, becomes small at potentials approaching Erev, and becomes positive (outward) at potentials more positive then Erev. - --- -## Measure postsynaptic (end plate) currents while stimulating motor neuron - -
voltage-clamping a postsynaptic muscle fiber
Neuroscience 5e Fig. 5.18
+## Acetylcholine +* The neurotransmitter used at the neuromuscular junction. Also used at synapses in visceral motor system and at some CNS synapses– called cholinergic neurons +* Synthesized from acetyl CoA and choline by choline acetyl transferase (ChAT)– its presence is a good indication that the neuron is cholinergic +* Removed from synapse by acetylcholine esterase (AChE) which has high activity– can cleave 5000 molecules per second +* Sarin "nerve gas" is a AChE inhibitor Note: -A postsynaptic muscle fiber is voltage clamped to control the muscle fiber’s membrane potential, while the presynaptic neuron is stimulated to cause ACh release at the end plate synapse. +ACh: skeletal muscle excitation vs release from vagus nerve that slows down heart beat (cardiac muscle)— +* Ligand gated channel that depolarizes skeletal muscle fibers vs g-protein coupled receptor that results in hyperpolarization of cardiomyocytes. + +Typical enzyme rates may be 1000 substrates molecules per second. AChE thought to be one of the fastest enzymes in the body. + +choline +: a water soluable essential nutrient +: quaternary ammonium salt +: present in plant and animal tissues +: choline is part of phophatidylcholine and sphingolipids (sphingomyelin in myelin) phospholipids on cell membranes +: also acetylcholine precursor + + +ACh discovery and WWI history timeline --- -## Hypothetical ion channel selectivities and the reversal potential - -
Current-voltage relationships for different ion selectivities
Neuroscience 2e 2001
- - -Note: - -So let’s imaging what the current-voltage relationships would look like for different channel selectivities. Remember the reversal potential is when there there is no net ion flux, so it 0 nA on all these graphs and if a channel is selective to only K, it would be equal to the Ek. - -If the channel was selective only to Na, than the Erev would be equal to ENa. Same for chloride. - -If the channel was a non-selective cation channel (passing both K and Na) then the current-voltage relationship would look like... - -11Na, 12Mg, 17Cl, 19K, 20Ca - - -*Ca2+ ions flow through CaV channels at a rate of ~106 ions s−1, but Na+ conductance is 500fold less through CaV channels* [#Tang:2014] -*extracellular [Na+] is nearly 70fold higher than Ca2+, thus Ca2+ selectivity is crucial* [#Tang:2014] -*Ca2+ and Na+ have nearly identical diameters (~2 Å)* 1 Å = 100 pm (Ca2+ larger atomic size, but Na+ has larger ionic size|hydration shell). -*Ca2+ selectivity is from high affinity binding, preventing Na+ permeability. Multi site pore, with knock on mechanism to push Ca2+ ions through* [#Tang:2014] - -[#Tang:2014]: Tang, L., Gamal El-Din, T. M., Payandeh, J., Martinez, G. Q., Heard, T. M., Scheuer, T., Zheng, N., and Catterall, W. A. (2014). Structural basis for Ca2+ selectivity of a voltage-gated calcium channel, Nature, 505(7481), 56-61. PMID 24270805 - - ---- - -## Postsynaptic Vm affects the magnitude and direction of end plate currents +## Acetylcholine synthesis
-
-Effect of Vm on postsynaptic muscle fiber end plate currents. -Inward current is down, outward current is up. -*Notice the current reverses at 0 mV* -
-
Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960
- +
Neuroscience 5e Fig. 6.2
Note: -These little transients are just stimulus artifacts, but look at the postsynaptic end plate currents in these at these different Vms. Look what happens when Vm is at 0mV, there is no current and then above 0 mV it flips from being inward to net outward current... +from krebs cycle you get Acetyl CoA. Na-Choline cotransporter exchanges Na ions for choline. -We already know that ACh is essential for the end plate currents-- therefore we can say that this EPC is IAch. Therefore what is the Erev for IAch? +choline acetyltransferase... +VAChT packs ACh into vesicles using the acidic vesicle's proton gradient. The gradient is established through active transport by the standard vacuolar H+-ATPase (V-ATPase), a highly conserved enzyme to convert ATP hydrolysis energy to proton transport across membranes. ---- - -## Postsynaptic Vm affects the magnitude and direction of end plate currents - -
Expected Erev if nAChR permeable only to K⁺, Cl⁻, or Na⁺
Neuroscience 5e Fig. 5.18
-
Observed Erev is in between Ek and ENa
Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960
- -Note: - -[#Takeuchi:1960]: Takeuchi, A. and Takeuchi, N. (1960). On the permeability of end-plate membrane during the action of transmitter, J Physiol, 154(), 52-67. PMID 13774972 - ---- - -## Shifting ENa+ or EK+ shifts Erev of the neuromuscular endplate current - -
Neuroscience 5e, Fig. 5.19, Takeuchi J Physiol 1960
- - -Note: - -So it seems that the ACh activated ion channels are equally permeable to Na and K and this was tested in 1960 by Akira and Noriko Takeuchi by changing the extracellular concentration of these ions. As predicted, lowering [Na] shifts Erev to the left and and raising the external [K] shifts Erev to the right. - ---- - -## What ions flow through the nACh receptor? - -
-
- -* Voltage clamping experiments show that there are large inward currents at -110 mV, smaller currents at -60 mV and no current at 0 mV. Outward currents at +70 mV. Therefore Erev = 0 -* Erev is not at any of the equilibrium potentials for a single ion, lies in between K⁺ (-100 mV) and Na⁺ (+70 mV) -* Altering the K⁺ concentration or the Na⁺ concentration will change the membrane potential. Therefore both Na⁺ and K⁺ are permeable through the nACh receptor -* nACh receptor can conduct both Na⁺ and K⁺ ions. The direction of flow is dependent on the membrane potential. The normal resting state of muscle is -100 mV, well below 0 mV (Erev) therefore normally at rest Na⁺ rushes in with very little K⁺ rushing out - -
- -Note: - -As we will see in a minute voltage clamp experiments show that there is a… - -Erev… - -Furthermore, altering… - -Therefore we can conclude that the nAChR can conduct both Na and K ions. - ---- - - -## Na⁺ and K⁺ movements during EPCs and EPPs - -
Neuroscience 5e Fig. 5.20
- -Note: - -Even though these ionotropic channels opened by ACh are permeable to both Na and K, at the resting membrane potential the EPC is generated primarily by Na influx because of the reduced driving force on K since at Vrest the membrane potential is closer to Ek. - -In fact the Na⁺ and K⁺ permeabilities of the nAChR channel are similar, therefore the **magnitudes of the Na⁺ and K⁺ currents depends on the driving forces present for each ion** -- -## Na⁺ and K⁺ movements during EPCs and EPPs - -
EPC: inward or outward; EPP: depolarizing or hyperpolarizing
Neuroscience 5e Fig. 5.20
- -Note: - -Here is the key: you get inward currents at potentials more negative the Erev and you get outward currents at potentials more positive than Erev. - -The resulting EPPs depolarize postsynaptic cell at potentials more negative than Erev and potentials more positive than Erev hyperpolarize the cell. - -*Since the Na⁺ and K⁺ permeabilities of this channel are similar, the magnitudes of the Na⁺ and K⁺ currents depends on the driving forces present for each ion* - - - ---- - -## nAChR summary - -* When the nAChR opens at normal resting potentials many Na⁺ ions rush in and a few K⁺ rush out. This causes a depolarizing EPP in the muscle cell. As the Vm during the EPP approaches Erev, outward K⁺ flux is equal to inward Na⁺ flux. Therefore if the nACh receptor is open long enough, it will drive Vm to Erev. -* If Erev is above action potential threshold, the probability of an action potential occurring is increased -* If Erev is below action potential threshold, the probability of an action potential occurring decreased - -Note: - -[http://www.nature.com/nrd/journal/v1/n6/full/nrd821.html: ](http://www.nature.com/nrd/journal/v1/n6/full/nrd821.html) - ->In the case of this modified muscle nAChR, the conductance of the pore is sensitive to the presence of negative charge at three locations that form three negatively charged rings in and near the M2 domain56. So, intensive studies of the M2 segment have been carried out to determine the amino acids that are responsible for the cationic or anionic selectivity of receptors. - ---- - -## Similar mechanisms exist at all chemical synapses - -For synapses between neurons: - -* Postsynaptic current (PSC) is similar to an end plate current -* Post synaptic potential (PSP) is similar to an end plate potential - * Excitatory PSP (EPSP)– increases likelihood of an action potential occurring - * Inhibitory PSP (IPSP)– decreases likelihood of an action potential occurring - -Note: - -So now let's generalize the properties that we’ve learned about EPCs through ionotropic AChR and their effects on EPPs at the neuromuscular junction to the case of chemical synapses between any pair of neurons... - -But instead of the so called EPPs, we'll call the postsynaptic potentials between neurons we call excitatory PSP if it increases the likelihood of an AP firing in a postsynaptic cell and inhibitory PSP if it decr the probability of an AP occurring in a postsynaptic cell. - - - - - ---- - -## EPSP summation - -* Unlike the neuromuscular junction– at synapses between neurons an individual EPSP is usually not very strong, typically well below threshold. -* Multiple EPSPs need to be summed together for the neuron's Vm to reach threshold. Individual neurons can receive thousands synapses. It's the summation of EPSPs and IPSPs that determine whether or not an action potential occurs. - -Note: - ---- - -## Excitatory postsynaptic potential (EPSP) - - - -
EPSP mediated by glutamate activating nonselective cation channels
Neuroscience 5e Fig. 5.21
- -Note: - -Imagine an experiment like the endplate potental recordings at the neuromuscular junction before but this time on a neuron in the CNS - ---- - -## Inhibitory postsynaptic potential (IPSP) type 1 - -
-
- -* An IPSP mediated by a GABA activated chloride selective channel that hyperpolarizes the neuron -* Reversal potential for the Cl⁻ current is negative to the resting potential and action potential threshold - -
- -
IPSP mediated by Cl⁻ selective ion channel
Neuroscience 5e Fig. 5.21
- -Note: - - ---- - -## IPSP type 2 - -* The reversal potential for the Cl⁻ current is positive to the resting potential but negative to threshold -* Activation of Cl⁻ channels depolarizes the neuron. Stabilizes membrane potential below threshold - -
IPSP mediated by Cl⁻ selective ion channel
Neuroscience 5e Fig. 5.21
-
EPSP: Erev > thresh, IPSP: Erev< thresh
Neuroscience 5e Fig. 5.21
- - -Note: - -Imagine if a separate EPSP input brought Vm of this neuron to -41 mV, just below -40mV threshold. Since this is now postive to the ECl of -50mV, further activity at the IPSP synapses will now hyperpolarize the neuron back towards -50mV. - -This can also be called shunting inhibition. In this case Na⁺ channels could persistently be in a state of inactivation due to small ongoing depolarizing and hyperpolarzing pulses keeping the neurons Vm below threshold. - -So just remember, the key is that if the Erev for the neurotransmitter receptor is more positive than threshold than it is excitatory. If it is more negative than threshold than it is inhibitory. - ->Blocking NKCC1 with bumetanide disrupts excitatory synapse development in the cortex - -*Bumetanide, a selective NKCC1 inhibitor, has been demonstrated to suppress certain forms of epileptiform activity in vitro and in vivo, presumably by attenuating the depolarizing effect of GABA (Dzhala et al., 2005; Kilb et al., 2007)* - ->effect of GABA on membrane polarity depends on the Cl gradient created by the expression of Na -K -2Cl cotransporter (NKCC) and K-Cl cotransporter (KCC). NKCC1 imports Cl and is expressed from the embryonic stage until the first postnatal week, whereas KCC2 exports Cl and is weakly expressed at birth and upregulated as the brain matures (Plotkin et al., 1997; Rivera et al., 1999; Li et al., 2002). The temporal expression patterns of these two transporters correspond to the switch of GABA from being excitatory to inhibitory during the first few weeks of rodent postnatal life (Delpire, 2000). - ---- - -## Summation of postsynaptic potentials - -
Neuroscience 5e Fig. 5.22
-
Neuroscience 5e Fig. 5.22
- -Note: - - - ---- - -## Summation - -* In general EPSPs in neurons are small 0.2–0.4 mV -* Most neurons are somewhere between 10–20 mV below threshold. If everything was linear that it would take the sum of 50 or so inputs to trigger AP -* Not so simple-- synaptic inputs can be summed in space and time within a neuron -* Recall a single neuron may have as many as 10,000 different synapses. Some are excitatory some inhibitory, some strong some weak. Some at the tips of dendrites, some near the cell body -* Integration of all these little postsynaptic bioelectric waves determines whether the neuron fires an action potential - -Note: - - - ---- - -## Neural integration +## AChE Inhibition
-* How does a neuron integrate all the information it is getting? -* In many neurons the decision to initiate an action potential is at the axon hillock. Contains a high density of voltage dependent Na^+^ channels and is contains membrane with lowest threshold -* Axon hillock is senses the local state of the cell, which is the combination of all the EPSPs and IPSPs going on at one time -* This is due graded potentials that spread passively -* Temporal summation, process by which consecutive synaptic potentials at the same site are added together. -* Spatial structure of the determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches +* Sarin and Soman: toxic irreversible AChE inhibitors. Also known as “nerve gases” for use in chemical warfare +* Designed to dispersed as a vapor cloud or spray, which allows their entry into the body through skin contact or inhalation. Drug quickly penetrates into bloodstream and is distributed to all organs, including the brain +* Symptoms: profuse sweating and salivating, uncontrollable vomiting, gasping for breath, convulsing, and gruesome death. These are due to rapid accumulation of ACh and overstimulation of cholinergic synapses throughout the CNS and PNS. Death occurs through asphyxiation due to paralysis of the muscles of the diaphragm + +
+ +
Psychopharmacology Chp. 6, 2006 Sinauer
+ + +Note: + +parasympathetic (Ach) vs sympathetic (norep) + +-- + +## Acetylcholine synthesis video summary + +
Neuroscience 5e Animation 6.1
+ +Note: + + +--- + +## Small molecule neurotransmitters + +
+
+ +* Acetylcholine +* Amino acids + * glutamate + * aspartate + * GABA + * glycine +* Monoamines + * dopamine + * norepinephrine + * epinephrine + * serotonin + * histamine +* Purines (ATP)
Note: -* Different synapses will have different time constants -* Some dendrites have voltage gated Na^+^ channels (albeit lower density than axons), these can amplify inputs -* Length constant of the cell determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches - -Time constant -: time needed for for resistive current (I~r~, current due to ions flowing through channels) and membrane potential (V~m~) to reach **63%** of their *asymptotic values* is proportional to the combination of resistance and capacitance of the circuit in question (across the cell membrane) -: membrane current (I~m~) is sum of I~r~ and the capacitive current (I~c~) -: I~m~ = I~r~ + I~c~ -: capacitance of membrane: during change in applied voltage or current across membrane, positively charged ions pile on surface of one side of membrane and **electrostatically** interact with cations on the other side of membrane surface (membrane acts as thin impermeable surfaces in parallel, like a capacitor), repeling them and inducing immediate, fast capacitive current along membrane -: capacitive current falls with an exponential time course. And the membrane potential rises with **same exponential** time course -: Relation of membrane potential at time *t* during charging of capacitance is given by V~t~ = V~inf~(1 - *e*^-t/RC^), where V~inf~ is the membrane potential at an infinite asymptotic value of the exponential curve. When t = RC, then we have V~t~ = V~inf~ ( 1 - *e*^-1^) ==> V~inf~ (0.63) - -```javascript -console.log( 1 - Math.E ** -1) -``` - - - - --- -## Summation of postsynaptic potentials video +## Glutamate -
Neuroscience 5e Animation 5.2
+* Most abundant neurotransmitter +* Nearly all excitatory neurons in the CNS are glutamatergic +* Does not cross the blood brain barrier +* Glutamine is most common precursor, glutaminase converts it to glutamate +* Retrieved from synapse by glutamate transporters in glia and neurons. Astrocytes turn glutamate to glutamine and spit it back out +* Too much glutamate can kill the post-synaptic neuron (excitotoxicity). A major problem after damage due to stroke + +Note: + +Most common neurotransmitter for normal brain function. Almost all excitatory neurons in CNS are glutamatergic. Half of all synapses estimated to use this transmitter. + +Glutamate (glutamic acid) is non-essential a.a. (meaning non-essential per dietary requirements) that does not cross the blood brain barrier. Synthesized inside neurons by local precursors. + +*Essential amino acids are: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine* + +*Monosodium glutamate (MSG, also known as sodium glutamate) is the sodium salt of glutamic acid* + +--- + +## Glutamate synthesis + +
+
+ +* synthesized from **glutamine** by **glutaminase** +* packaged into vesicles by vesicular glutamate transporters (**VGLUT**) using proton gradient setup by V-ATPase +* removed from cleft by excitatory amino acid transporter **EAAT** +* converted into glutamine by glutamine synthetase in the glial cell +* tranported back to neuron via system N transporter 1 (**SN1**) and system A transporter 2 (**SAT2**) + + +
+ +
Neuroscience 5e Fig. 6.5
+ + +Note: + +Metabolized into glutamate by mitochondrial enzyme glutaminase. Also glucose metabolism from Krebs cycle can also produce glutamate. + +Packaged into vesicles by vesicular glutamate transporters (VGLUT). 3 different VGLUTs identified. + +Removed from cleft by excitatory a.a. transporters (EAATs). These are family of 5 Na⁺ dependent glutamate cotransporters. Some in glial cells, some in presynaptic terminals. + +Glutamate in glial cells by EAAT converted into glutamine by enzyme glutamine synthetase. + +Glutamine then transported out by different transporter system N transporter 1 (SN1) then back into nerve cells by system A transporter 2 (SAT2). +-- + +## Glutamate synthesis video summary + +
Neuroscience 5e Animation 6.2
+ +Note: + +ACh role in Alzheimers: basal forebrain innervation to neocortex vs hippocampus. Cholinergic neuron degradation vs local postsynaptic neuron effects… + +--- + +## GABA and glycine + +* Inhibitory neurons primarily use GABA or glycine +* Activation of GABA or glycine receptors typically reduces probability of firing action potentials +* GABA (gamma-aminobutyric acid)– made from glutamate by glutamic acid decarboxylase (GAD) + * GAD requires Vitamin B6 as cofactor +* Glycine– about 1/2 of neurons in spinal cord use glycine +* Hyperglycinemia– defect in glycine uptake and removal leading to severe mental retardation + +Note: + +As many as a third of synapses in the brain use GABA as an inhibitory transmitter. Most commonly found in local circuit neurons. + +glycine encephalopathy: + +from [http://ghr.nlm.nih.gov/condition/glycine-encephalopathy](http://ghr.nlm.nih.gov/condition/glycine-encephalopathy): + +>Glycine encephalopathy, which is also known as nonketotic hyperglycinemia or NKH, is a genetic disorder characterized by abnormally high levels of a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body. A lack of this enzyme allows excess glycine to build up in tissues and organs, particularly the brain, leading to serious medical problems. + +-- + +## Glycine + +* Inhibitory neurotransmitter +* Makes the post-synaptic membrane more permeable to Cl⁻. Can result in hyperpolarization of the post-synaptic cell +* Glycine receptor is primarily found in the ventral spinal cord +* Strychnine + * glycine receptor antagonist which can bind to the receptor without opening the Cl⁻ channel (i.e. it inhibits inhibition) + * spinal hyperexcitability + +
*Strychnos nux-vomica*
+ +Note: + +Strychnine +: highly toxic, colorless, bitter crystalline alkaloid +: from *Strychnos nux-vomica* native to India, Sri Lanka, and Indonesia + +--- + +## GABA synthesis + +
+
+ +* synthesized from glutamate by glutamic acid decarboxylase (**GAD**) +* transported into vesicles by vesicular inhibitory amino acid transporter (**VIAAT**), using proton gradient setup by V-ATPase. +* Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called **GATs** + +
+ +
Neuroscience 5e Fig. 6.8
+ +Note: + +synthesized from glutamate by glutamic acid decarboxylase (**GAD**) + +transported into vesicles by vesicular inhibitory amino acid transporter (**VIAAT**), using proton gradient setup by V-ATPase. + +Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called **GATs** + +-- + +## Glycine synthesis + +
Neuroscience 5e Fig. 6.8
+ +Note: + +Synthesized from glucose by serine hydroxy-methlytransferase (**GAD**) + +Transported into vesicles by vesicular inhibitory amino acid transporter (**VIAAT**), using proton gradient setup by V-ATPase. + +Removal by neurons and glia by Na⁺ dependent glycin cotransporters **GATs** + + +Taurine and beta-alanine (other amino acids) can act as agonists for glycine receptors and also gaba receptors to some degree [Mori:2002] + + +[Mori:2002]: Mori M., Gahwiler B. H. and Gerber U. (2002) Beta-alanine and taurine as endogenous agonists at glycine receptors in rat hippocampus in vitro. J. Physiol. 539, 191–200 + +--- + +## Small molecule neurotransmitters + +
+
+ +* Acetylcholine +* Amino acids + * glutamate + * aspartate + * GABA + * glycine +* Monoamines + * dopamine + * norepinephrine + * epinephrine + * serotonin + * histamine +* Purines (ATP) + +
+ +Note: + +--- + +## Monoamine neurotransmitters (biogenic amines) + +* Catecholamines– dopamine, norepinephrine, and epinephrine + * All derived from tyrosine. Tyrosine hydroxylase is the rate limiting step and is a good histological marker for catecholaminergic neurons +* Histamine +* Serotonin +* Are implicated in many complex behaviors + +Note: + + +**Monoamines** (a subset of biogenic amines. Biogenic amines are monoamines + trace amines like like tryptamine, phenethylamine, melatonin) regulate many functions in the CNS and PNS. Ranging from homeostatic functions to cognition and attention. + +* All come from same synthesis pathway +* defects in function implicated in many psychiatric disorders +* targets of many drugs of abuse + +*Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group.* + +- *reserpine used as antipsychotic, depletes Norep at synaptic terminals by blocking vesicle loading* +- *organic structure template: R—NH2* + +-- + +## Catecholamine synthesis + +
Neuroscience 5e Fig. 6.10
+ + +Note: + +--- + +## Dopamine + +* Produced by the enzyme DOPA decarboxylase +* Made by substantia nigra pars compacta (which connects to corpus striatum for coordination of body movements) +* Does not cross the blood brain barrier, but levadopa (L-DOPA) does +* Parkinson’s treatments include L-DOPA plus degradation enzyme inhibitors +* Cocaine works by inhibiting the dopamine cotransporter DAT + +Note: + +Synthesized in cytoplasm of presynaptic terminals. + +Loaded into synaptic vesicles by vesicular monoamine transporter (VMAT). Dopamine in synaptic cleft is terminated by reuptake of dopamine into nerve terminals or glia cells by a Na-dependent dopamine cotransporter called DAT. Cocaine works by inhibiting DAT, increasing dopamine concentrations in synaptic cleft. + +Amphetamine also inhibits DAT as well as a transporter for norepinephrine + +* Catabolized by monoamine oxidase and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT. Inhibitors of these enzymes are targets of some kinds of antidepressants (phenelzine and tranylcypromine) +* Acts throught GPCRs. D3 parallels that of other metabotropic receptors like mAChR. Subtypes act by activating or inhibiting adenylyl cyclase. +* Activation leads to complex behaviors. Antagonists can cause catalepsy (state where difficult to initiate voluntary movement). +* L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. +* it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase. + +*Parkinson's treatment: LDOPA + enzyme inhibitors info* +*blood brain barrier info* + +*Encephalitis lethargica, sleeping sickness, 40 yrs later Oliver Sacks in NYC treats them with L-DOPA* + +* neostriatum +* Part of + * Basal ganglia + * Reward system +* Components + * Ventral striatum + * Dorsal striatum + +The corpus striatum, a macrostructure which contains the striatum, is composed of the entire striatum and the globus pallidus. The lenticular nucleus refers to the putamen together with the globus pallidus. + + + + +--- + +## Projections from dopaminergic neurons in the human brainstem + +
Neuroscience 5e Fig. 6.11
+ + +Note: + + +-- + +## Dopamine synthesis video summary + +
Neuroscience 5e Animation 6.3
+ +Note: + + +--- + +## Norepinephrine + +* also called noradrenaline +* Comes from dopamine by way of dopamine-β-hydroxylase +* Sympathetic ganglion cells use it– project to visceral motor system (fight or flight response) +* Used as a transmitter from locus coeruleus in brainstem (rostral pons)– projects to areas that are involved in sleep, attention, and feeding +* Its reuptake mechanism, the norepinephrine transporter (NET), is a target of amphetamines + +Note: + +VMAT for loading into vesicles + +Norep transporter (NET) is a Na⁺ depedent cotranporter. NET is a target of amphetamines. + +alpha and beta adrengergic receptors. GPCRs. Some alphas lead to slow depolarization. Some lead to slow hyperpolarization (acting on different K⁺ channels). + +norepinephrine also released into blood by adrenal medulla of adrenal gland + +locus coeruleus +: input– hypothalamus, cingulate cortex, amygdala, cerebellum, raphe nuclei +: output– everywhere, spinal cord, brainstem, cerebellum, hypothalamus, thalamus, amygdala, cerebral cortex +: activation mediates an excitatory effect, giving rise to arousal/wakefulness + + +--- + +## Projections from noradrenergic neurons in the human brainstem + +
Neuroscience 5e Fig. 6.11
+ + +Note: + + +-- + +## Norepinephrine synthesis video summary + +
Neuroscience 5e Animation 6.4
+ +Note: + + + +* Epinephrine/Adrenaline– present at lower levels than the others +* Epinephrine made by neurons in rostral medulla. Project to thalamus and hypothalamus + +--- + +## Epinephrine + +* Adrenaline– present at lower levels than the others +* Made by neurons in rostral medulla. Project to thalamus and hypothalamus + +-- + +## Projections from adrenergic neurons in the human brainstem + +
Neuroscience 5e Fig. 6.11
+ + + +--- + +## Serotonin + +* 5-hydroxytryptamine (5-HT) +* Made from tryptophan +* Reuptake by specific serotonin transporters +* Many antidepressants act by inhibiting serotonin reuptake (selective serotonin reuptake inhibitors-SSRIs; e.g. Prozac, Zoloft) +* Found primarily in groups of neurons in the raphe region of the pons and upper brainstem +* The raphe nucleus projects widespread in forebrain areas that are implicated in sleep and wakefulness and mood + + +Note: + +* dorsal raphe and median raphe nuclei. In brain stem. raphe nuclei just ventral to the 4th ventricle stretching from medulla +* vesiclular monoamine transporter **VMAT** loads this (as well as other monoamines) into synaptic vesicles. + +turkey/tryptophan—> sleep? Yes— but not really ([http://www.snopes.com/food/ingredient/turkey.asp](http://www.snopes.com/food/ingredient/turkey.asp)), you’d have to eat a lot more (maybe 3x more) than at a particular meal. And furthermore, lots of protein sources include amounts of tryptophan similar to or greater than that of turkey per gram of food content (including eggs, fish, cheese, and some nuts, seeds, legumes). Tryptophan is present in all proteins, but is also + +And besides well timed carbohydrate ingestion with/after tryptophan consumption is important for increasing tryptophan transport from blood vessels and into brain tissue: + +[http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2](http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2): + +>The small, all-carbohydrate snack is tryptophan's ticket across the blood-brain barrier, where it can boost serotonin levels. + +Tryptophan competes with other large aromatic neutrally charged amino acids for passage into brain from blood vessels. But tryptophan is the only amino acid known to bind non-covalently with serum albumin (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1133271/?page=1) (Curzon, 1973; Smith and Pogson, 1980). This is thought to protect it from insulin induced cellular metabolism (insulin rising after eating carbohydrates of course) by bringing tryptophan to high enough concentrations in blood to favor entry into brain. Indicates that the timing of carbohydrate ingestion may be helpful. + +Study looking at food/protein composition type and quantitative mesaures of cerebral serotonin levels after consumption (5-HT levels can change 8-fold in rat): https://doi.org/10.1016/j.physbeh.2009.05.004 + + + +--- + + +## Histamine + +* Made from histidine, a metabolite of monoamine oxidase +* Released by neurons in hypothalamus (tuberomammilary nucleus) that send projections to all parts of the brain and spinal cord +* Mediates arousal and attention +* Histamine receptors are in the immune system and in the CNS. Sedative effects of diphenhydramine (Benadryl) act through the CNS + + +Note: + +* synthesized from histidine by + +* H1 receptors (antagonists used for treating motion sickness because role in vestibular function) +* H2 receptors control secretion of gastric acid in digestive system + +*transported into vesicle by VMAT as catecholamines* + + +diphenhydramine +: benadryl +: inhibits H1 receptors +: also has some serotonin reuptake inhibitor capability +: also has some anticholinergic (muscarinic) capability + +--- + +## Projections from serotonergic and histaminergic neurons + +These projections are sparse (low synapse density) but widespread (most brain regions). + +
+
histaminergic axons from tuberomamillary nucleus of hypothalamus, +serotonergic axons from dorsal raphe nucleus of brain stem +
+
Neuroscience 6e Fig. 6.17, 5e Fig. 6.13
+ +-- + + +## Synthesis of histamine and serotonin + +
Neuroscience 5e Fig. 6.14
+ +Note: + +--- + +## Peptide neurotransmitters + +* 3-36 or so amino acids, cleaved from larger precursor proteins +* Catabolized by peptidases +* 5 general classes, brain/gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing hormones, all others +* Packaged into large dense-core vesicles +* Generally used as co-transmitters + +Note: + +* Many peptides known to be hormones also act as neurotransmitters +* melanocyte-stimulating hormone, adrenocorticotropin, Beta-endorphin regulate complex responses to stress +* substance P and opioid peptides involved in the perception of pain + +-- + +## Amino acid sequences of peptide neurotransmitters + +
Neuroscience 5e fig. 6.17
+ +Note: + + +--- + +## Synthesis of neuropeptides + +* Neuropeptides are synthesized as pre-propeptides in the nerve cell bodies +* This includes a signal sequence that targets the peptides to the inside of the endoplasmic reticulum +* The signal sequence is cleaved to form the propeptide + +Note: + + +-- + +## Synthesis of neuropeptides + +
Neuroscience 5e Fig. 6.16
+ +Note: + +Proteolytic processing of the pre-propeptides, pre-proopiomelanocortin and pre-proenkaphalin + +Processing the polypeptides that make the final neuropeptdies happens in an neurons cell body. Propeptide packaged into vesicles in golgi network. Final peptide processing occurs after packaging into vesicles. Multiple neuroactive peptides can be released from a single vesicle. + +proopiomelanocortin +: precursor for melanocyte-stimulating hormone, adrenocorticotropin, beta-endorphin +: regulate complex responses to stress and modulation of pain +: beta-endorphin binds to mu-opioid receptors + +ACTH +: adrenocorticotropic hormone +: corticotropin +: secreted by anterior pituitary gland +: produced in response to stress +: increases production of cortisol in adrenal glands + + + + + + +--- + +## Examples of peptide transmitters– Opioids + +* Bind to same post-synaptic receptors as opium +* Family with more than 20 members, three basic groups: endorphins, enkephalins, and dynorphins +* Often co-localized with GABA and serotonin +* Tend to act as depressants, used for analgesics +* Repeated use often leads to tolerance and addiction + +Note: + +Opioids are named because they bind to same postsynaptic receptors as opium. + +* opium poppy cultivated for 5000 yrs +* opium contains a variety of plant alkaloids, predominantly morphine. Morpheus, greek god of dreams. Very effective analgesic. Fentanyl, synthetic opiate with 80 times analgesic potency of morphine + +Opioid peptides distributed throughout the brain. Colocalize with GABA and 5-HT. Tend to be depressants. They act like analgesics when injected intracerebrally. Initiate effects through GPCRs. Activate at low concentrations (nM to uM). mu, delta, kappa opioid receptor subtypes play role in reward and addiction. mu-receptor is primary site for opiate drugs. + +TODO: opiate drug info + +Naloxone is a non-selective and competitive opioid receptor antagonist. + +-- + +## Examples of peptide transmitters– Substance P + +* Substance P– 16 amino acid peptide +* Present in human hippocampus, neocortex, and GI tract (hence a brain-gut peptide) +* Involved in the perception of pain +* Released from C-fibers which carry information about pain and temperature + +Note: + +accidental discovery of substance P. Ominous sounding compound from Area 51? No. It was an unidentified component of powder extracts from brain and intestine. High conc. in hippocampus, neocortex, and GI tract. A brain/gut peptide. Release of Subst P in cfibers can be inhibited by spinal interneurons releasing opioid peptides. + + + + +--- + +## Unconventional neurotransmitters– cannabinoids + +
+
+ +* Cannabinoids + * Endocannabinoids + * anandamide + * 2-arachidonylglycerol (2-AG) + * Δ9-tetrahydrocannabinol (THC) + * main psychoactive compound in *cannabis sativa*/*indica* +* Bind to G-protein coupled receptors (GPCRs): CB1 & CB2 +* CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum + +
+ +
+
Anandamide
+
2-AG
+
THC
+
+ + +Note: + +Unconventional neurotransmitters. Released from neurons, regulated by Ca²⁺, and have specific receptors, but not released from synapses by exocytotic vesicle mechanisms. Often unconventional NTs are associated with retrograde signaling from post to pre. + +These endocannabinoids are actually unsaturated fatty acids from enzymatic digestion of membrane lipids. Production stimulated by second messengers within postsynaptic neuron, typically a rise in postsynaptic Ca²⁺ concentration. + +Ohno-Shosaku *Neuron* 2001: endocannabinoids act on cannabinoid receptors (CB1) to reduce GABA release from presynaptic inhibitory neurons. Inhibiting inhibition (disinhibition). + +-anandamide +-2-arachidonylglycerol (2-AG) + +[Anandamide](https://en.wikipedia.org/wiki/Anandamide) +: N-arachidonoylethanolamine +: essential fatty acid neurotransmitter +: derived from non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid, an essential ω-6 polyunsaturated fatty acid) +: effects can occur in either CNS or PNS +: effects by CB1 cannabinoid receptors in the CNS and CB2 cannabinoid receptors in the PNS [#Pacher:2006] +: CB2 receptors involved in regulating immune system function +: found in chocolate [#Tomaso:1996] +: endocannabinoids, long chain fatty acids like anandamide found in drosophila melanogaster [#Jeffries:2014] but cannabinoid receptors are not [#McPartland:2001] + +[#Pacher:2006]: Pacher, P., Bátkai, S., and Kunos, G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy, Pharmacol Rev, 58(3), 389-462 + +[#Tomaso:1996]: di Tomaso, E., Beltramo, M., and Piomelli, D. (1996). Brain cannabinoids in chocolate, Nature, 382(6593), 677-8 + +[#Jeffries:2014]: Jeffries, K. A., Dempsey, D. R., Behari, A. L., Anderson, R. L., and Merkler, D. J. (2014). Drosophila melanogaster as a model system to study long-chain fatty acid amide metabolism, FEBS Lett, 588(9), 1596-602 + +[#McPartland:2001]: McPartland, J., Di Marzo, V., De Petrocellis, L., Mercer, A., and Glass, M. (2001). Cannabinoid receptors are absent in insects, J Comp Neurol, 436(4), 423-9 + +Mechanism of release not clear, but likely that these hydrophobic signals diffuse through the postsynaptic membrane to reach cannabinoid receptors on nearby cells. Action terminated by carrier mediated transport into postsynaptic neuron and hydrolyzed by enzyme fatty acid amide hydrolase (FAAH). + +Psychotropic +: psychoactive +: chemical substance that changes brain function resulting in altered perception, mood, or conciousness + +* cannabis sativa | cannabis indica + * used for hemp (fiber, oil, seed) + * phytocannabinoids (85 active identified in cannabis) + +THC: +* agonist of both CB1 and CB2 +* mild to moderate analgesic effects (dorsal root ganglion and PAG), antiemetic (anti-nausea) +* tolerance appears to be irregular throughout mouse brain areas +* possesses mild antioxidant activity +* Bioavailability 10–35% (inhalation), 6–20% (oral)[3] +* Protein binding 97–99%[3][4][5] +* Metabolism Mostly hepatic by CYP2C[3] +* Biological half-life 1.6–59 h,[3] 25–36 h (orally administered dronabinol) +* Excretion 65–80% (feces), 20–35% (urine) as acid metabolites[3] + +cannabidiol: a major phytocannabinoid, accounting for up to 40% of the plant's extract. More complex effects than THC, may potentiate effects through CB1 density increases, inhibition of FAAH. Allosteric modulator of mu-opioid receptors. Less understood. + +cannabinol: higher affinity for CB2 (but weaker than THC). Breakdown product of THC + +-rimonabant, synthetic drug + +GPCRs: + +CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum + +CB2 expressed in cells throughout the immune system. T cells, macrophages, B cells, peripheral nerve terminals (relief of pain), microglial cells + +major CB2 targets are: >immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kupffer cells in the liver, etc. + +>multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).[25] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.[#Demuth:2006] + +inhibits inhibition on presynaptic GABAergic neurons. Inhibits IPSCs. disinhibitory effect. + +[#Demuth:2006]: Demuth DG, Molleman A (2006). "Cannabinoid signalling". Life Sci. 78 (6): 549–63. doi:10.1016/j.lfs.2005.05.055. PMID 16109430. + +Other cannabinoid-like compounds found in other plants (e.g. Echinacea). Some like b-caryophyllene (volatile plant terpene) are quite common among plants (incl cannabis sativa) and act as agonist (nM concentrations) of CB2 [#Gertsch:2010]. Most of these that have been found so far have affinities for CB2. Mostly just THC with non-selective affinity for CB1 (and CB2 modulation) at nM concentrations so far. But Falcarinol also has non-selective CB1 affinity (at µM concentrations) [#Gertsch:2010], and is widespread in Apiaceae (celery, carrot, parsley family) like *Daucus carota* also in red ginseng *Panax ginseng*) though it might work as an inverse agonist. + +[#Gertsch:2010]: Gertsch, J., Pertwee, R. G., and Di Marzo, V. (2010). Phytocannabinoids beyond the Cannabis plant - do they exist?, Br J Pharmacol, 160(3), 523-9 + +*Apiaceae* +: angelica, anise, arracacha, asafoetida, caraway, carrot, celery, Centella asiatica, chervil, cicely, coriander (cilantro), culantro, cumin, dill, fennel, hemlock, lovage, cow parsley, parsley, parsnip, cow parsnip, sea holly, giant hogweed and silphium + +*Daucus carota* +: wild carrot +: 'Queen Anne's lace' +: domesticated carrots are cultivars of a subspecies + +-- + +## CB1 receptors are expressed widely throughout the forebrain + +
CB1 expression in rodent
Neuroscience 5e Box 6. M. Herkenham, NIMH
+ + + +Note: + +TODO: +* human expression evidence +* human rodent brain comparison + +--- + +## Summary + +
Neuroscience 5e Table 6.1