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neurophysiology1.md
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@@ -784,7 +784,7 @@ Note:
---
## K⁺ concentration gradient determines resting membrane potential
## K⁺ concentration gradient largely determines resting membrane potential
<figure><img src="figs/Neuroscience5e-Fig-02.08-0_40bc007.png" height="400px"><figcaption>
@@ -799,7 +799,7 @@ They plotted resting membrane potential against the extracellular K⁺ concentra
If internal K⁺ is unchanged, a plot of membrane potential against the log of external K⁺ concentration would yield a straight line with slope of 58mV per tenfold change in external K⁺ concentration at RT.
However it deviates from this expected relationship (shown by the black line), especially at lower K⁺ concentrations. Why is this?
However it deviates from this expected relationship (shown by the black line), especially at lower K⁺ concentrations. Why?
**Because other ions, particularly Cl⁻ and Na⁺, are also slightly permeable and the contribution of these other ions is more evident at low K⁺ concentrations.**
@@ -915,13 +915,14 @@ And as we will soon learn, the resting membrane potential and action potential v
## The action potential– summary
<figure><img src="figs/action_potential_ab5134f.png" width="800px"><figcaption></figcaption></figure>
<figure><img src="assets/fig_AP.svg" width="800px"><figcaption></figcaption></figure>
Note:
And this is just a overall summary of what we have been discussing
<!--
## Action potential form and nomenclature
@@ -937,16 +938,13 @@ AHP due to voltage-gated K⁺ channels, including Ca²⁺ activated potassium ch
## Action potential forms
<div><figcaption class="big">(1) Frog motor neuron cell body, (2) guinea pig inferior olive neuron cell body, (3) cell body of purkinje neuron</figcaption><img src="figs/Neuroscience5e-Box-02C-0-2_f48aa34.png" width="800px"><figcaption>Neuroscience 5e Box 2C</figcaption></div>
Summation of many spikelets cause unlike most neurons, purkinje cells in cerebellum have dendrites that can initiate action potentials. The dendrites aren’t myelinated.
Summation of many spikelets, cause unlike most neurons, purkinje cells in cerebellum have dendrites that can initiate action potentials.
Llinas Sugimori J Physiol 1980 Purkinje neurons

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neurophysiology2.md
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@@ -115,11 +115,22 @@ The current flowing back into the axon and thus across its membrane can be measu
**This electronic feedback circuit** holds the membrane potential at the desired level, even in the face of permeability changes that would normally alter the membrane potential. (such as those generated during the action potential). Most importantly, the device permits the simultaneous measure of the current needed to keep the cell at a given voltage. This current is exactly equal to the amount of current flowing across the neuronal membrane, allowing direct measurement of these membrane currents.
>An amplifier, electronic amplifier or (informally) amp is an electronic device that can increase the power of a signal. It does this by taking energy from a power supply and controlling the output to match the input signal shape but with a larger amplitude.
amplifier, electronic amplifier
: "amp"
: electronic device that can increase the power of a signal
: uses energy from a power supply and controls an output signal to match input signal shape, but with greater amplitude
>A differential amplifier is a type of electronic amplifier that amplifies the difference between two input voltages but suppresses any voltage common to the two inputs.[1]
differential amplifier
: type of electronic amplifier
: amplifies difference between two input voltages and suppresses any voltage common to the two inputs
: op-amp
>An operational amplifier (often op-amp or opamp) is a DC-coupled high-gain electronic voltage amplifier with a differential input and, usually, a single-ended output.[1] In this configuration, an op-amp produces an output potential (relative to circuit ground) that is typically hundreds of thousands of times larger than the potential difference between its input terminals.[2]
operational amplifier
: <https://en.wikipedia.org/wiki/Operational_amplifier>
: "op-amp"
: DC-coupled electronic amplifier
: differential input and often a single output
: can produce an output potential many thousands of times larger than the voltage difference between inputs
---
@@ -144,9 +155,13 @@ So the experiment was to hold the membrane potential at different voltages and m
## Electric current flow across a squid axon membrane during voltage clamp
<div><figcaption class="big">negligible current (except for a capacitive transient)</figcaption><img src="figs/Neuroscience5e-Fig-03.01-1R_5455913.png" height="300px"><figcaption>Neuroscience 5e/6e fig. 3.1; from Hodgkin et al., *J. Physiol.* 1952</figcaption></div>
<div><figcaption class="big">negligible current (except for a capacitive transient)</figcaption><img src="figs/Neuroscience5e-Fig-03.01-1R_5455913.png" height="300px"><figcaption>
<div><figcaption class="big">inward and outward currents</figcaption><img src="figs/Neuroscience5e-Fig-03.01-2R_49ec352.png" height="300px"><figcaption>Neuroscience 5e/6e fig. 3.1; from Hodgkin et al., *J. Physiol.* 1952</figcaption></div>
Neuroscience 5e/6e fig. 3.1; from Hodgkin et al., *J. Physiol.* 1952</figcaption></div>
<div><figcaption class="big">inward and outward currents</figcaption><img src="figs/Neuroscience5e-Fig-03.01-2R_49ec352.png" height="300px"><figcaption>
Neuroscience 5e/6e fig. 3.1; from Hodgkin et al., *J. Physiol.* 1952</figcaption></div>
<div style="font-size:0.7em; margin:25px 0;">Inward current is always downward deflection from zero in these traditional voltage clamp plots. Outward current is an upward deflection. </div>
@@ -180,7 +195,9 @@ However when Hodgkin and Huxley depolarized the membrane, a transient inward cur
## Inward & outward currents produced at a series of clamped membrane voltages
<figure><figcaption class="big">Voltage clamp recordings from squid axon. Capacitive artifact removed for clarity.</figcaption><img src="figs/Neuroscience5e-Fig-03.02-0_5ee332f.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.2; from Hodgkin et al., *J. Physiol.* 1952</figcaption></figure>
<figure><figcaption class="big">Voltage clamp recordings from squid axon. Capacitive artifact removed for clarity.</figcaption><img src="figs/Neuroscience5e-Fig-03.02-0_5ee332f.png" height="400px"><figcaption>
Neuroscience 5e/6e Fig. 3.2; from Hodgkin et al., *J. Physiol.* 1952</figcaption></figure>
Note:
@@ -196,7 +213,12 @@ Notice a few phenonmena in this figure.
## Relationship between current amplitude and membrane potential
<figure><figcaption class="big">External Na⁺ 440 mM, internal Na⁺ 50 mM, therefore Nernst says **E<sub>Na</sub> = 55 mV**</figcaption><img src="figs/voltage_clamp_currents_summary_plot_7450e0a.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.3; from Hodgkin et al., *J. Physiol.* 1952</figcaption></figure>
<figure><figcaption class="big">
External Na⁺ 440 mM, internal Na⁺ 50 mM, therefore Nernst says **E<sub>Na</sub> = 55 mV**</figcaption>
<img src="figs/voltage_clamp_currents_summary_plot_7450e0a.png" height="400px"><figcaption>
Neuroscience 5e/6e Fig. 3.3; from Hodgkin et al., *J. Physiol.* 1952</figcaption></figure>
Note:
@@ -222,7 +244,9 @@ So it seems like this inward current may be carried by Na ions.
## Dependence of the early inward current on sodium
<div><img src="figs/Neuroscience5e-Fig-03.04_0d877f5.png" height="500px"><figcaption>Neuroscience 5e/6e Fig. 3.4; from Hodgkin and Huxley *J. Physiol.* 1952a</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-03.04_0d877f5.png" height="500px"><figcaption>
Neuroscience 5e/6e Fig. 3.4; from Hodgkin and Huxley *J. Physiol.* 1952a</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/Wd_gKJoo25Y" width="420" height="315"></iframe><figcaption>Squid giant axon voltage clamping</figcaption></div>
@@ -267,17 +291,20 @@ Note:
</div>
<div><img src="figs/1f421_8622cf0.png" height="300px"><figcaption>puffer fish</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/4g8KeqjSyqg" width="420" height="315"></iframe><figcaption>Simpsons poison tasty fish</figcaption></div>
<!-- <div><iframe src="https://www.youtube.com/embed/4g8KeqjSyqg" width="420" height="315"></iframe><figcaption>Simpsons poison tasty fish</figcaption></div> -->
Note:
Its mechanism of action, selective blocking of the sodium channel, was shown definitively in 1964 by Toshio Narahashi and professor John W. Moore at Duke University, using the sucrose gap voltage clamp technique (Narahashi et al, J Gen Physiol 1964)
Its mechanism of action, selective blocking of the sodium channel, was shown definitively in 1964 by Toshio Narahashi and professor John W. Moore at Duke University, using the voltage clamp technique (Narahashi et al, J Gen Physiol 1964)
---
## Pharmacological separation of inward and outward currents into Na⁺ and K⁺ dependent components
<figure><img src="figs/Neuroscience5e-Fig-03.05-0_99fe22f.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.5; from Moore et al. *J Gen Physiol* 1967 and Armstrong and Binstock *J Gen Physiol* 1965</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-03.05-0_99fe22f.png" height="400px"><figcaption>
Neuroscience 5e/6e Fig. 3.5; from Moore et al. *J Gen Physiol* 1967 and Armstrong and Binstock *J Gen Physiol* 1965</figcaption></figure>
Note:
@@ -330,7 +357,9 @@ Can use this to calculate the dependence of Na and K conductances vs. time and m
## Membrane conductance changes are time and voltage dependent
<div><img src="figs/Neuroscience5e-Fig-03.06-0_757dbce.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.6; from Hodgkin and Huxley *J Physiol* 1952b</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-03.06-0_757dbce.png" height="400px"><figcaption>
Neuroscience 5e/6e Fig. 3.6; from Hodgkin and Huxley *J Physiol* 1952b</figcaption></div>
Note:
@@ -341,7 +370,9 @@ Note:
## Depolarization increases Na⁺ and K⁺ conductances of the squid giant axon
<div><img src="figs/Neuroscience5e-Fig-03.07-0_fdae974.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.7; from Hodgkin and Huxley *J Physiol* 1952b</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-03.07-0_fdae974.png" height="400px"><figcaption>
Neuroscience 5e/6e Fig. 3.7; from Hodgkin and Huxley *J Physiol* 1952b</figcaption></div>
Note:
@@ -386,7 +417,7 @@ Can also see increases in K conductance during the AP, but this K+ conductance (
---
## Properties of action potentials explained
## Properties of action potentials
<div style="font-size:0.8em;">
<div></div>
@@ -401,11 +432,11 @@ 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 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.
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 more or less order (or less or more disorder) is the point of criticality, often knownas a phase transition.
---
## Properties of action potentials explained
## Properties of action potentials
* Action potential propagation and directionality?
* Refractory periods?
@@ -413,7 +444,6 @@ The threshold is a point of criticality in the system like trying to balance on
Note:
Next we will look at the following properties of APs such as:
---
@@ -424,24 +454,27 @@ Next we will look at the following properties of APs such as:
Note:
First let’s talk about AP propagation.
During an action potential, inward current through Na⁺ channels
During an action potential, inward current is mediated by Na⁺ influx through sodium channels.
---
## Passive current flow in an axon
## Decay of subthreshold signals
<figure><figcaption class="big">subthreshold changes decay rapidly</figcaption><img src="figs/Neuroscience5e-Fig-02.03-1R_aac41b9.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.3</figcaption></figure>
A subthreshold depolarization (like a synaptic potential) decays in amplitude with increasing distance and time from its site of origin (e.g. dendrite branch) on a neuron.
<figure><figcaption class="big">subthreshold changes decay</figcaption><img src="figs/Neuroscience5e-Fig-02.03-1R_aac41b9.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.3</figcaption></figure>
Note:
Subthreshold signals. Currents underlying subthreshold signals are also called passive current flow in textbook, or electrotonic decay.
bottom graph shows the peak Vm
---
## Propagation of an action potential
## Propagation of regenerative suprathreshold signals
<figure><figcaption class="big">suprathreshold depolarizations propagate down the axon and don't decay</figcaption><img src="figs/Neuroscience5e-Fig-02.03-2R_4bea3b6.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.3</figcaption></figure>
@@ -486,7 +519,7 @@ Active and Passive current flow.
</div>
<div><img src="figs/action_potential_ab5134f.png" height="150px"><figcaption></figcaption></div>
<div><img src="assets/fig_AP.svg" height="150px"><figcaption></figcaption></div>
Note:
@@ -518,6 +551,15 @@ Note:
Note:
myelin
: appears to have arisen independently across evolution in vertebrates, annelids, and crustacea
: for vertebrates, likely first present in ancestor of sharks and bony fish
: not present in ancient vertebrates like hagfish and lampreys
: not present in molluscs or insects thus far
[^Hartline2007]: Hartline and Colman Curr Biol, 2007. <http://www.sciencedirect.com/science/article/pii/S0960982206025231>
---
## Nodes of Ranvier
@@ -552,9 +594,11 @@ red indicates imaged expression of voltage gated Na channels. green indicates a
Note:
figure comparing action potential propagation speed in an unmyelinated and myelinated axon.
Comparing action potential propagation speed in an unmyelinated and myelinated axon. In either case, a sufficient density of voltage-gated sodium channels must be expressed along the axon membrane. <!-- todo: how many? -->
action potential genaration occurs only at specific points, the nodes of Ranvier, along the myelinated axon
Regeneration of a spike waveform (action potential) occurs all along the axon (perhaps think of an infinite number of spots).
Regeneration of a spike waveform occurs at specific points along a myelinated axon, the nodes on the axons in between myelin sheaths (the nodes of Ranvier).
--
@@ -573,7 +617,9 @@ 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?
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
@@ -619,4 +665,3 @@ Note:
Note:

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@@ -15,7 +15,7 @@ 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.
Now we know from our previous classes covering the work by HH, that there are some predictions we make concerning the nature of ion channels:
Now we know from our previous classes covering the work by Hodgkin-Huxley, that there are some predictions we make concerning the nature of ion channels..
--
@@ -31,21 +31,6 @@ During the rising phase of the action potential:
Note:
So a quick question
Answer to myelinated question from last time:
[Hartline and Colman Curr Biol, 2007](http://www.sciencedirect.com/science/article/pii/S0960982206025231)
>It seems to have arisen independently in evolution several times in vertebrates, annelids and crustacea.
>absent in primitive members of the vertebrate line (hagfish and lampreys)
>Myelin has not been reported in either molluscs or insects
>The first myelinated vertebrate was likely to have been a placoderm [9], the antecedent of contemporary sharks and bony fish.
---
@@ -73,22 +58,25 @@ Can measure ion flow through a single channel.
Note:
---
--
## The patch clamp method
<div style="height:300px"><figcaption>Neuroscience 5e Box 4A</figcaption><img src="figs/Neuroscience5e-Box-04A-2R_58077da.jpg" height="200px"><figcaption class="big">
Can measure potentials and currents
from entire cell and introduce
things into the cytoplasm
</figcaption></div>
<div style="margin:0 25px; height:300px"><figcaption>Neuroscience 5e Box 4A</figcaption><img src="figs/Neuroscience5e-Box-04A-3R_8f113be.jpg" height="200px"><figcaption class="big">
Makes it easy to introduce things to
the cytoplasmic side of the channel
</figcaption></div>
<div><figcaption>Neuroscience 5e Box 4A</figcaption><img src="figs/Neuroscience5e-Box-04A-4R_1677b63.jpg" height="200px"><figcaption class="big">
<div style="margin:33px 0;"><figcaption>Neuroscience 5e Box 4A</figcaption><img src="figs/Neuroscience5e-Box-04A-4R_1677b63.jpg" height="200px"><figcaption class="big">
Makes it easy to introduce things to the extracellular side of the channel
</figcaption></div>
@@ -147,7 +135,8 @@ TEA
<div>
<div></div>
* Small inward currents
* Small (picoampere) inward currents
* Unitary amplitudes
* Open at beginning of pulse
* Inactivate quickly
@@ -158,12 +147,17 @@ TEA
Note:
Patch a piece of membrane and block K currents. Do a bunch of short recordings while clamping the membrane at depolarized potential. e.g. here is 7 trials. Notice the amplitude is discrete— it is unitary. If you were recording from lots of these single channels simultaneously or added together all the recordings from one channel you'd -->
Patch a piece of membrane and block K currents. Do a bunch of short recordings while clamping the membrane at depolarized potential. e.g. here is 7 experimental trials. **Notice the amplitude is discrete**— it is unitary. If you were recording from lots of these single channels simultaneously or added together all the recordings from one channel you'd -->
Transient channel opening in Na⁺ channels (inward current).
This research is from Bezanilla and Correa 1995, Vandenburg and Bezanilla 1991, Correa and Bezanilla 1994
unitary (wn, adj)
: one, unitary -- (having the indivisible character of a unit; "a unitary action"; "spoke with one voice")
---
## Measurements of ionic currents flowing through single Na⁺ channels
@@ -182,13 +176,12 @@ This research is from Bezanilla and Correa 1995, Vandenburg and Bezanilla 1991,
Note:
get something similar to this microscopic current shown at the top.
Average the microscopic currents together and you get something very similar.
Average the microscopic currents together and you get something very similar to this macroscopic voltage-clamp current shown at the top.
Sum these microscopic inwa
Notice that even at -20 to -10mV when you expect an action potential to be well into its rising phase above threshold, the probability of sodium channel opening is just 40-50% (and never reaches 100%).
This research is from Bezanilla and Correa 1995, Vandenburg and Bezanilla 1991, Correa and Bezanilla 1994
Bezanilla and Correa 1995, Vandenburg and Bezanilla 1991, Correa and Bezanilla 1994
---
@@ -268,7 +261,6 @@ Remember this figure from last time, shown here is a model of the functional sta
Note:
So the conclusions are…
---
@@ -375,13 +367,19 @@ from [channelpedia](http://channelpedia.epfl.ch/ionchannels/9):
>a voltage-activated A-type potassium ion channel and is prominent in the repolarization phase of the action potential. This gene is expressed at moderate levels in all tissues analyzed, with lower levels in skeletal muscle.
HERG channels inactivate so rapidly that current flows only when inactivation is rapidly removed at end of a depolarization
- inward rectifier K channels allow more K current to flow at hyperpolarized potentials than at depolarized potentials
* human Ether-à-go-go-Related Gene), best known for its contribution to the electrical activity of the heart that coordinates the heart's beating, mediates the repolarizing IKr current in the cardiac action potential).
* HERG channels inactivate so rapidly that current flows only when inactivation is rapidly removed at end of a depolarization
inward rectifier K channels allow more K current to flow at hyperpolarized potentials than at depolarized potentials
Ca activated K channels open in response to intracellular Ca ions
2-P K channels usually respond to chemical signals rather than changes in membrane potential. These are primarily responsible for the resting membrane potential of neurons. e.g. TASK channels can by regulated by extracellular pH
2-P K channels ("two-pore", or KCNK gene family, 50+ genes?) can respond to other signals (e.g. pH changes for the TASK (KCNK3 and KCNK9) channel subtypes) rather than changes in membrane potential and are important in regulating the ongoing membrate potential of neurons at "rest", playing a role in the historically termed "K<sub>leak</sub>" current.
<https://www.nature.com/articles/35058574>
<!-- ## Diverse properties of K⁺ channels
@@ -398,7 +396,6 @@ inward rectifier K channels allow more K current to flow at hyperpolarized poten
Ca activated K channels open in response to intracellular Ca ions
2-P K channels usually respond to chemical signals rather than changes in membrane potential. These are primarily responsible for the resting membrane potential of neurons. e.g. TASK channels can by regulated by extracellular pH
-->
@@ -518,7 +515,9 @@ K | 0.27 | 0.46
</div>
<div><img src="figs/K-channel-selectivity-filter_cf5a63c.jpg" width="300px"><figcaption>JA, [CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)</figcaption></div>
<div><img src="figs/K-channel-selectivity-filter_cf5a63c.jpg" width="300px"><figcaption>
JA, [CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)</figcaption></div>
Note:
@@ -617,21 +616,8 @@ Yellow are voltage sensing tm domains
4–8 positively-charged amino acids in the S4 domain. Experiences force in a transmembrane electric field. Is the electric-field sensor for voltage-dependent gating.
K channels are more diverse
K channels are diverse
- Kv2.1 show little inactivation and are closely related to the delayed rectifier K channels involved in AP repolarization
- Kv4.1 channels inactivate during a depolarization.
HERG channels inactivate so rapidly that current flows only when inactivation is rapidly removed at end of a depolarization
* human Ether-à-go-go-Related Gene), best known for its contribution to the electrical activity of the heart that coordinates the heart's beating, mediates the repolarizing IKr current in the cardiac action potential).
inward rectifier K channels allow more K current to flow at hyperpolarized potentials than at depolarized potentials
Ca activated K channels open in response to intracellular Ca ions
2-P K channels usually respond to chemical signals rather than changes in membrane potential. These are primarily responsible for the resting membrane potential of neurons. e.g. TASK channels can by regulated by extracellular pH
<!-- Channel selectivity

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@@ -3,7 +3,11 @@
* Synapses– functional contacts between neurons
* Two general classes– chemical and electrical synapses
* Chemical– neurons talk to each other by release of neurotransmitters
* Electrical– direct, passive flow of current between neurons
* Electrical– **direct** flow of current between neurons
<div style="font-size:0.5em;">
<!-- date: -->
</div>
Note:
@@ -36,17 +40,19 @@ Note:
## Electrical synapses
* Less common than chemical synapses
* The cell membranes of two cells are linked together via gap junctions
* Current flows **directly** from one neuron to another via gap junctions– form large pores between cells made up of connexin proteins
* The cell membranes of two cells are linked together via **gap junctions**
* Current flows **directly** from one neuron to another via gap junctions– form large pores (compared to ion channels) between cells made up of connexin proteins
* The signal is very fast– the only limit is diffusion
* Signals can go in both directions
* Are used to synchronize electrical activity among populations of neurons
* Function to **synchronize** electrical activity among populations of neurons
Note:
We have a quadrillion synapses, 10^15 in our nervous system. A tiny fraction are electrical synapses.
These electrical synapse or gap junction synapses are thought to be more common among inhibitory interneurons in the brain—
quadrillion synapses, 10^15 in our nervous system
Pore is approx 1 nm in diameter. Allows passage of small molecular weight substances like intracellular metabolites (a few hundred daltons), but not proteins (typically 5-500 kilodaltons in diameter)
---
@@ -60,35 +66,26 @@ Note:
* connexins— extracellular loops and disulfide bridges
* 3.5nm separating the apposed lipid bilayers connected through connexon hemichannels
* 20-40nm separation at a chemical synaptic cleft
* passive ionic current flow, small substance like ATP and second messengers
- versus 20-40nm separation at a chemical synaptic cleft
* passive ionic current flow, small substances like ATP and second messengers can pass through
<!-- <img src="figs/image1_e4cc3f1.png" height="300px"> -->
Current in the presynaptic cell is not felt directly by post-synaptic cell for a chemical synapse.
--
## Electrical synapses
<figure><img src="figs/Neuroscience5e-Fig-05.02-1R_copy_2f541cc.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.3, 5e Fig. 5.2; from Fushpan and Potter, 1959 </figcaption></figure>
In contrast to gap junctions/electrical synapses, for chemical synapses current flow does not occur directly from the presynaptic cell to postsynaptic cell.
Note:
gap junction proteins:
connexins (chordates), innexins (invertebrates), and also pannexins. Similar topologies but dissimilar gene/amino acid sequences.
In Crayfish an action potential in one neuron spreads quickly to the next in fraction of a millisecond.
connexins : 20 isoforms in humans and mice. 40 connecxin orthologues across species. Cx36 36kDa protein, hexamer possibly only forming hemichannels homotypically, specific to neurons. [^Connors:2004]. Cx36 KO mouse has no obvious behavioral phenotype other than retinal deficits[^Connors:2004].
--
50% of mammalian connexins widely expressed in CNS. Some strong in astrocytes (Cx26,30,43) or oligodendrocytes (Cx29,32,47) [^Connors:2004]
## Electrical synapses
gap junctions first found and studied in invertebrates. Innexins for gap junctions in drosophila, c elegans molluscs, annelids, playhelminthes. Mammalian pannexin genes are similar to innexins and Px1 and Px2 mRNA is present in pyramidal neurons and interneurons of the hippocampus.
<figure><img src="figs/Neuroscience5e-Fig-05.02-2R_copy_3cd5bb0.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.3, 5e Fig. 5.2; from Beierlein et al. 2000 </figcaption></figure>
c elegans: 959 total cells in adult hermaphrodite. 302 are neurons, 58 are glia. Every cell in worm expresses innexins, most of the 20+ isoforms are expressed in nervous system and every neuron is believed to form gap junctions. 7000 synapses. 6393, 890 electrical junctions. 1410 NMJ.
Note:
In hippocampal neurons gap junctions can make neurons fire in synchrony
---
@@ -103,40 +100,28 @@ In hippocampal neurons gap junctions can make neurons fire in synchrony
Note:
quadrillion synapses, 10^15 in our nervous system
Electrical synapses could play an important role in diseases of pathological oscillations/synchrony like childhood epilepsy.
important in diseases of pathological oscillations/synchrony like childhood epilepsy, etc
Electrical synapses and synchronization of activity is characteristic of cells that stimulate pulses of pituitary hormones (e.g oxytocin/vasopressin secretion).
Electrical synapses and synchronization characterisitc of cells that stimulate pulses of pituitary hormones (e.g oxytocin/vasopressin secretion).
Important for neuronal networks in the pons, medulla: nucleus ambiguous, pre-botzinger complex, solitary nucleus
medulla and pons, medulla: nucleus ambiguous, pre-botzinger complex, solitary nucleus
Inferior olivary nucleus: source of climbing fiber input to cerebellar cortex. ultrastructure and electrophysiology (Llinas 1974) found electrical coupling between pairs of neurons in cat inferior olive. Same thing demonstrated later in guinea pig, rat, mouse. Also dye coupling evidence between neurons. 2-8Hz synchronous oscillations. [^Connors:2004]
inferior olivary nucleus: source of climbing fiber input to cerebellar cortex. ultastructure adn ephys (Llinas 1974) found electrical coupling between pairs of neurons in cat inferior olive. Same thing demonstrated later in guinea pig, rat, mouse. Also dye coupling. 2-8Hz synchronous oscillasions. [^Connors:2004]
Thalamic reticular nucleus (thin interneuron layer) of dorsal thalamus. Spatially localized electrical coupling (cells 40 um apart). [^Connors:2004]
thalamic reticular nucleus (thin interneuron layer) of dorsal thalamus. Spatially localized coupling (cells 40 um apart). [^Connors:2004]
Hippocampus. between pyramidal neurons and also interneurons. [^Connors:2004]
hippocampus. between pyramidal neurons and also interneurons. [^Connors:2004]
In neocortex only rarely found between pyramidal neurons, often between interneurons. 'Late spiking' L1 interneurons make electrical synapse with other neurons of the same class 83% of time but with other interneuron types only 2% of time. Maybe necessary for gamma frequency rhthyms.
in neocortex only rarely found between pyramidal neurons, often between interneurons. 'Late spiking' L1 interneurons make electrical synapse with other neurons of the same class 83% of time but with other interneuron types only 2% of time. Maybe necessary for gamma frequency rhthyms.
retina has widespread electrical coupling. Extensive between amacrine cells, scoptopic vision impaired in Cx36 KO mice from loss in rods and cones and between amacrine cells and bipolar cells.
The retina has widespread electrical coupling. Extensive between the amacrine cells (interneurons) that synthesize GABA, acetylcholine as neurotransmitter), scoptopic vision impaired in Cx36 KO mice from loss in rods and cones and between amacrine cells and bipolar cells.
Cx36 in both olfactory epithelium and olfactory bulb. between granule cells. between mitral cells in same glomerulus.
Early in development, first postnatal week in rat electrical coupling extensive between motor neurons in spinal cord. Declines during first postnatal week but still present in adult.
gap junction proteins:
connexins (chordates), innexins (invertebrates). Similar topologies but dissimilar gene/amino acid sequences. Also pannexins in
connexins : 20 isoforms in humans and mice. 40 connecxin orthologues across species. Cx36 36kDa protein, hexamer possibly only forming hemichannels homotypically, specific to neurons. [^Connors:2004]
50% of mammalian connexins widely expressed in CNS. Some strong in astrocytes (Cx26,30,43) or oligodendrocytes (Cx29,32,47) [^Connors:2004]
gap junctions first found and studied in invertebrates. Innexins for gap junctions in drosophila, c elegans molluscs, annelids, playhelminthes. Mammalian pannexin genes are similar to innexins and Px1 and Px2 mRNA is present in pyramidal neurons and interneurons of the hippocampus.
gap junctions may be sensitive to Ca2+ influx, at least at high concentrations. But are very sensitive to small intracellular (but not extracellular) pH changes and intracellular pH changes occur doing neuronal activity.
Gap junctions may be sensitive to Ca2+ influx, at least at high concentrations. But are very sensitive to small intracellular (but not extracellular) pH changes and intracellular pH changes occur doing neuronal activity.
[^Connors:2004]: https://www.annualreviews.org/doi/10.1146/annurev.neuro.26.041002.131128
@@ -144,17 +129,38 @@ Carbenoxolone (from licorice root) not very specific for Cx36.
Quinine selectively blocks Cx36,50,45. Mefloquine is a derivative that is 100x more potent.
--
Cx36 KO mouse has no obvious behavioral phenotype other than retinal deficits[^Connors:2004].
## Electrical synapses
<figure>
<figcaption class="big">Synchronous spikes between two crayfish neurons</figcaption>
<img src="figs/Neuroscience5e-Fig-05.02-1R_copy_2f541cc.jpg" height="400px"><figcaption>Neuroscience 6e Fig. 5.3, 5e Fig. 5.2; from Fushpan and Potter, 1959 </figcaption></figure>
Note:
In Crayfish an action potential in one neuron can spread quickly to the next in fraction of a millisecond.
--
## Electrical synapses
<figure>
<figcaption class="big">Synchronous spikes between a pair of mammalian hippocampal neurons</figcaption>
<img src="figs/Neuroscience5e-Fig-05.02-2R_copy_3cd5bb0.jpg" height="400px"><figcaption>Neuroscience 6e Fig. 5.3, 5e Fig. 5.2; from Beierlein et al. 2000 </figcaption></figure>
Note:
In hippocampal neurons, gap junctions can make neurons fire in synchrony
c elegans: 959 total cells in adult hermaphrodite. 302 are neurons, 58 are glia. Every cell in worm expresss innexins, most of the 20+ isoforms are expressed in nervous system and every neuron is believed to form gap junctions. 7000 synapses. 6393, 890 electrical junctions. 1410 NMJ.
---
## Chemical synapses
* The majority of connections use chemical synapses
* They form at the synaptic cleft
* Majority of connections use chemical synapses
* Form at the synaptic cleft
* Presynaptic cells have synaptic vesicles that have neurotransmitters in them
* Post-synaptic cells have neurotransmitter receptors on the plasma membrane
@@ -165,13 +171,21 @@ Note:
## Synapse structure as seen by electron microscopy
<div><figcaption class="big">chemical synapse, type 1</figcaption><img src="figs/image2_1bf4990.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">chemical synapse, type 1</figcaption><img src="figs/image2_1bf4990.png" height="220px"><figcaption>
<div><figcaption class="big">chemical synapse, type 2</figcaption><img src="figs/image3_5af29bc.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">synaptic vesicles</figcaption><img src="figs/image4_b39a9f7.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">chemical synapse, type 2</figcaption><img src="figs/image3_5af29bc.png" height="220px"><figcaption>
<div><figcaption class="big">synaptic cleft</figcaption><img src="figs/image5_a67adf4.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">synaptic vesicles</figcaption><img src="figs/image4_b39a9f7.png" height="220px"><figcaption>
[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">synaptic cleft</figcaption><img src="figs/image5_a67adf4.png" height="220px"><figcaption>
[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
Note:
@@ -235,11 +249,19 @@ Note:
Note:
The vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve). It also has some afferent fibers that innervate the inner (canal) portion of the outer ear (via the auricular branch, also known as Alderman's nerve) and part of the meninges.
Vagus nerve (/ˈveɪɡəs/ vay-gəs)
: responsible for many things
: heart rate, gastrointestinal peristalsis, sweating, and some muscle movements in the mouth, including speech (via the recurrent laryngeal nerve)
: supplies motor parasympathetic fibers to all organs except the supra-renal (adrenal) glands, from the neck down to the second segment colon
: historically called the pneumogastric nerve
: is the tenth cranial nerve
: regulates parasympathetic control of the heart and digestive tract
: vagus nerves are paired but often referred as singular
: has some afferent fibers that innervate the inner portion of the outer ear
: afferent fibers in vagus nerve innervating the pharynx, responsible for gag reflex
The vagus nerve (/ˈveɪɡəs/ vay-gəs), historically cited as the pneumogastric nerve, is the tenth cranial nerve or CN X, and interfaces with parasympathetic control of the heart and digestive tract. The vagus nerves are paired; however, they are normally referred to in the singular.
The vagus nerve supplies motor parasympathetic fibers to all the organs except the suprarenal (adrenal) glands, from the neck down to the second segment of the transverse colon. The vagus also controls a few skeletal muscles, notable ones being:
vagus nerve
skeletal muscles controlled by vagus nerve include:
* Cricothyroid muscle
* Levator veli palatini muscle
@@ -249,12 +271,6 @@ The vagus nerve supplies motor parasympathetic fibers to all the organs except t
* Superior, middle and inferior pharyngeal constrictors
* Muscles of the larynx (speech).
*This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve).*
*It also has some afferent fibers that innervate the inner (canal) portion of the outer ear (via the auricular branch, also known as Alderman's nerve) and part of the meninges. This explains why a person may cough when tickled on the ear, such as when trying to remove ear wax with a cotton swab.[citation needed]*
*Afferent vagus nerve fibers innervating the pharynx and back of the throat are responsible for the gag reflex.*
---
@@ -270,7 +286,7 @@ Otto Loewi, 1921
Free acetylcholine acts on **muscarinic receptors** which **hyperpolarize** the cells of the SA node and slow the conduction of the action potential through the AV node. This slows heart rate. Acetylcholine also decreases Ca2+ influx which lowers the heart's force of contraction.
This figure no longer is in 6e.
This figure no longer is in 6e of textbook.
--
@@ -305,11 +321,10 @@ Note:
Note:
* curare used as a paralyzing poison by South American indigenous peoples for hunting that causes respiratory asphixiation (diaphragm muscle paralysis) in prey
* alkaloid arrow poisons that are competitive and reversible inhibitors of nicotinic acetylcholine receptor (nAChR)
* ACh action has same pharmacology as vagus nerve substance in that it is sensitive to curare (a plant poison that kills by preventing muscle contraction). Competes with curare for receptor binding
- Curare used as a paralyzing poison by South American indigenous peoples for hunting that causes respiratory asphixiation (diaphragm muscle paralysis) in prey
- Curare is a plant alkaloid that is a competitive and reversible inhibitors of nicotinic acetylcholine receptor (nAChR)
---
@@ -454,7 +469,7 @@ Note:
* Bath in low calcium and stimulate you get small subthreshold EPPs that are about the same size as the MEPPs.
* Examination of the muscle membrane potential at high gain reveals small, spontaneous depolarizations. These are miniature end plate potentials (MEPPs)
This work was on frog neuromuscular junc in 1950s but subsequent investigations have demosntrated these synaptic properties for all chemical synapses studied to date.
This work was on frog neuromuscular junc in 1950s but subsequent investigations have demonstrated these synaptic properties for all chemical synapses studied to date.
---
@@ -483,6 +498,9 @@ If you measure the amplitudes of these small low calcium EPPs and plot their dis
Poisson statistics used to analyse independent occurence of unitary events. Red curve shows what the distribution would expected to be if neurotransmitter release is quantal, made up of discrete message packets (vesicles) made of multiples of MEPP amplitudes (e.g. 0.4 mV)
quantum, quanta (wn, noun)
: ((physics) the smallest discrete quantity of some physical property that a system can possess (according to quantum theory))
---
## Quantal neurotransmission
@@ -516,10 +534,10 @@ Note:
* All that vesicle fusion– why doesn’t the membrane keep growing and growing?
* Synaptic vesicle membranes get recycled quickly
* Are endocytosed in clathrin coated vesicles which fuse to endosome and bud off again
* Can use a pulse chase experiment to show this
Note:
Can use a pulse chase experiment to show this -->
--
@@ -530,8 +548,8 @@ Note:
Note:
(Experiments by Heuser and Reese, 1973). HRP enzyme forms dense reaction product, can be visualized easily in electron microscopy.
Pulse chase experiments by Heuser and Reese, 1973. HRP enzyme forms dense reaction product, can be visualized easily in electron microscopy.
Clathrin has a unique three arm structure that forms little geodesic dome coverings around membrane segments and dynamin forms a ring that pinches or 'buds' off the vesicle.
@@ -558,6 +576,7 @@ Note:
Note:
Calcium flux is essential for chemical synaptic neurotransmission.
--
@@ -584,7 +603,7 @@ block Na⁺/K⁺ currents with TTX/TEA
Note:
(Augustine and Eckert 1984)
experiment done in giant squid (Augustine and Eckert 1984)
--
@@ -611,7 +630,7 @@ Note:
*Fluorescent dye that binds calcium (Smith et al 1993)*
*squid giant axon from contacts the contractile muscular mantle responsible for water expulsion and squid jet propulsion*
*squid giant axon contacts the contractile muscular mantle responsible for water expulsion and squid jet propulsion*
---
@@ -720,21 +739,33 @@ Model based on crystal structure work for SNAP25 from Sutton 1998, Madej 2014, Z
Note:
[from https://en.wikipedia.org/wiki/Botulinum_toxin:](https://en.wikipedia.org/wiki/Botulinum_toxin:)
* cleavage of SNARE proteins inhibits acetylcholine release
* botulinum toxins specifically cleave SNAREs, preventing synaptic vesicles from docking and fusing with plasma membrane
* blocking release of acetylcholine results in flaccid paralysis of muscles (typical of botulism)
* [https://en.wikipedia.org/wiki/Botulinum_toxin](https://en.wikipedia.org/wiki/Botulinum_toxin)
>Cleavage of the SNARE proteins inhibits release of acetylcholine.[45] Hence, botulinum toxins A, B, and E specifically cleave SNAREs, preventing "neurosecretory vesicles" from docking/fusing with the interior surface of the plasma membrane of the nerve synapse, and so block release of neurotransmitter. In inhibiting acetylcholine release, nerve impulses are blocked, causing the flaccid (sagging) paralysis of muscles characteristic of botulism[45]
* tetanus toxin cleaves the synaptobrevin SNARE protein within spinal cord interneurons. This results in less inhibition of spinal cord motor neurons giving rise to muscle hyperexcitation and "tetanic" contractions
Thus two definitions for tetanus from wordnet, one referring to the bacterial toxin and one referring to a hyperexcitable phenotype in muscle tissue:
tetanus (wn, noun)
: an acute and serious infection of the central nervous system caused by bacterial infection of open wounds; spasms of the jaw and laryngeal muscles may occur during the late stages
: a sustained muscular contraction resulting from a rapid series of nerve impulses
Thus in animal physiology when discussing sustained excitation of muscle tissue, it may be referred as "tetanic" stimulation or a muscle "in tetanus".. even when there is no tetanus toxin.
--
## Synaptic vesicle toxins
Tetanus toxin and various types of botulinum toxin act by preventing exocytosis.
Tetanus toxin and botulinum toxins act by cleave synaptic SNARE proteins, preventing exocytosis.
<figure><figcaption class="big">SNARE protein sites cleaved by tetanus and botulinum toxins</figcaption><img src="figs/Neuroscience5e-Box-05B-2-0_copy_0d09c20.jpg" height="400px"><figcaption>Neuroscience 5e Box 5B, see also Clinical Application 6e p. 99-100</figcaption></figure>
Note:
Tetanus toxin and botulinum toxins are all from *Clostridium* bacteria.
<!-- ## Botox
@@ -743,8 +774,6 @@ Note:
<figure><img src="figs/photo_botox_behandlung_a000d47.jpeg" height="200px"><figcaption></figcaption></figure>
when botox is injected in small amounts, it can effectively weaken a muscle for a period of three to four months
-->
@@ -757,11 +786,3 @@ when botox is injected in small amounts, it can effectively weaken a muscle for
Note:
<!--
## Midterm thursday
* Similar format as the practice midterm
* 100 points total, 25% of your grade
* Covers material in lectures 1–6
-->