Action Potentials

Fox, Chapter 7 (mostly)

Spike propagates nondecrimentally long distances

Fig 7.4
Typical nerve
Most important information - axon is relatively long.
There are various shapes.
Top - this looks likes the input to the spinal, the cell is in the dorsal root ganglion
Middle - there are bipolar neurons in the retina
Bottom - this looks like the spinal motor neuron, cell in ventral horn of spinal cord gray matter.
In this multipolar neuron, synapses are on dendrites and cell body, axon carries action potential

Fig. 7.11
Figure
oscilloscope essentially graphs voltage as a function of time
The figure introduces the terms depolarization and hyperpolarization

Properties of the action potential

Fig. 7.13
(What everybody should remember about the action potential based on the background you are assumed to have.)
At threshold, Na+ channels open (then close), and Na+ diffuses in
After peak of action potential (spike), K+ channels open, and K+ diffuses out
The spike is all-or-none, as opposed to having variable sizes like synaptic potentials or receptor potentials.
After the spike, there is a refractory period (when another spike cannot be started), and this insures unidirectional propagation.
Note that the depolarization to threshold shows the membrane acting as a low pass filter.

Fig. 7.19
Spike depolarises the axon ahead of it to depolarize the membrane to threshold

Passive propagation

Introduction. "Action" potential refers to the active voltage-gating that opens the Na+ channel that allows nondecremental propagation. If that did not happen, propagation would be decremental based on the passive spread of current going down the axon and also leaking out the membrane.

Fig. 7.19 (again)
(look back, I already showed it)
Current going down axoplasm and leaking out membrane
The recorded potential gets smaller

Figure
pdf
Cable equation

Summary:
(1) an action potential at one place depolarizes the membrane ahead of it to threshold.
(2) the spread is passive.
(3) current down the axoplasm leaks out through membrane resistance and capacitance.
(4) solving, space constant varies with square root of radius, time constant independent of radius.
(5) that is why invertebrates use giant axons for fast propagation.

Myelin speeds up the action potential

Fig. 7.7
Transmission electron micrograph (TEM) of myelin.
Membrane is wrapped around and cytoplasm is squeezed out, leaving only alternating bands of electron density and lucency at high magnification.
Each layer of membrane has high resistance, and resistors in series block current flow through membrane.
Each layer of membrae has high capacitance which would leak current, but capacitors in series add reciprocally, decreasing capacitance and leakage.

Fig. 7.20
Myelinated axons have faster propagation.
Invertebrates do not have myelin, and that is why they have giant axons.
Here's why: action potential jumps from one node of Ranvier to next, "saltatory" (leaping) conduction

Myelin is invested by different cells in peripheral vs central nervous systems

Fig. 7.6
In PNS (peripheral nervous system), myelin is made from multiple membrane wrappings of Schwann cell.
One axon
Disrupted in polio (poliomyelitis)

Polio (poliomyelitis) is a viral disease that damages myelin in peripheral nervous system causing paralysis; then the nerve cell degenerates.
Salk (1955, injected) then Sabin (eat sugar cube) vaccines in the 1950s, before that, only passive immunity from gamma globulin from people who had polio.
Serious cases required an iron lung.
FDR had polio.
Neuron's trophic effect on muscle is seen as muscle (not directly diseased) deteriorates.

Recent literature
It is thought that there is some recovery where motor neurons branch more (they already branch to innervate all of the muscle cells [fibers] of one motor unit) so that surviving neurons
innervate muscle cells "abandoned" by lost nerve cells.
But at middle age, there is increased fatigue, pain and weakness (post-polio syndrome).
Cause: those sprouts are lost.
L.S. Halstead Post -polio syndrome, Scientific American, April 1998 42-47

Fig. 7.8
In CNS (central nervous system), myelin is formed from oligodendrocytes.
Multiple axons, hence the prefix "oligo" (a few).
Disrupted in multiple sclerosis.

Multiple sclerosis (MS) (Anette Funicello, Montell Williams, Richard Prior, "the president" in West Wing) damages myelin in the central nervous system
Might aflict motor function, vision, or others
Hits people 20-40, with deterioration but sometimes episodic, i.e. with remissions
Animal model - EAE (experimental allergic [autoimmune] encephalitis) to myelin basic protein.
Such a disorder used to happen with rabies vaccination when virus was gron in brain (before it was grown in eggs).

Hodgkin Huxley Nobel experiments

Fig. 7.14
resting potential is based on predominant K+ permeability
then Na+ channels activate
then Na+ channels inactivate
then a late K+ channel activates

Channels

GENERALIZATION - action potential is based on Na+ and K+
there are MANY other channel types

Fig. 7.12
inactivation is "stopper" on chain

Tetrodotoxin puffer fish (saxitoxin dinoflagellates) block Na+ channel

Questions from 2004 - 2011 that relate to this outline

Reminder: The Goldman equation looks like the Nernst equation except that it includes concentrations (in and out) plus permeabilities for all three ions - Na+, K+ and Cl-. Only one of these 9 values changes at the beginning of the action potential. Which?

permeability for Na+

Discussing the sodium channel, say something about (1) A stopper on the N-terminus of the protein, or (2) puffer fish and dinoflagellates.

(1) responsible for inactivation (2) toxin from these blocks sodium channel

What does an oscilloscope allow you to measure that a voltmeter with a needle does not?

voltage as a function of time for fast events like spikes

"The multiple layers of membrane in myelin have less capacitance than one layer of membrane would have." How would the resistance of multiple layers relate to the resistance of one layer?

multiple layers would be much higher

Immune system, say something about one of the following: (1) Active immunity, polio. (2) Passive immunity, polio. or (3) Multiple sclerosis.

1 you would get this from a vaccine or from having the disease 2 you would get it from being injected with antibodies 3 you develop autoimmunity to myelin basic protein, a self protein

In saltatory (leaping) conduction, the action potential jumps from where to where?

one node of Ranvier to the next

How is the direction that the action potential travels along the axon regulated by the refractory period of the action potential?

the refractory period keeps it from going backward (back to where it had already been)

For post-polio syndrome (worsening symptoms in middle age), according to a paper discussed in class, why is there (answer either) (1) a recovery after the initial infantile paralysis, or (2) the worsening symptoms in middle age?

spinal motor neurons sprout to connect to abandoned muscle fibers, these sprouts go away

What is the molecular mechanism for channel inactivation?

a stopper formed by amino acids near the n-terminus plugs the channel

"For passive spread of voltage along the axon, the time constant is independent of the axon radius." Then how come large invertebrate axons are faster than small ones?
 
The space constant varies with the square root of the radius
 
Oh sure, myelin ought to be a good insulator on the basis of the many layers of resistance, but what about capacitance?
 
Since capacitors in series add reciprocally, the many layers decrease capacitance, also making myelin a good insulator
 
If multiple sclerosis (MS) is caused by immunity to a protein in myelin, how come everybody does not have MS?
 
Autoimmunity is from the immune surveillance "seeing" a protein that is sequestered from surveillance in most people

You apply a depolarization (below threshold for triggering an action potential) at a certain place along the axon. Why would it get smaller the further away from this place that you
record?

because current leaks out through the membrane

What is a disease of central nervous system myelin?

multiple sclerosis

What electrical properties of myelin contribute to saltatory conduction?

R & C

Permeability to what ion increases at the beginning of the action potential?

sodium

According to cable equation calculations, how does the speed of propagation relate to the radius of the axon?

square root of radius

Describe a difference between an oligodendrocyte and a Schwann cell.

myelinate several vs one axon, also CNS vs PNS

After the nerve cell integrates the excitatory and inhibitory post-synaptic potentials, which part of the cell propagates the action potential (if threshold is reached)?

axon

Invertebrates do not have myelin. What adaptation allows for fast action potentials in invertebrates?

giant axons

If current from a depolarizing stimulus travels down the axoplasm, how come the recorded voltage would get smaller with increasing distance from the stimulus (according to the passive, "cable" properties)?

because current leaks out through membrane resistance and capacitance

What property keeps the action potential from triggering an action potential behind it as it travels down the axon?

refractory period

How does the capacitance of the multiple layers of membrane in myelin compare with the the capacitance of one layer of membrane of an axon?

capacitance in series adds inversely, so, fortunately, multiple layers have less

Why is the muscle smaller when it is innervated by a nerve damaged by polio?

because the nerve has a trophic effect on the muscle

What happens to the size of the action potential as you go along the axon?

it is all-or-none, always the same

What does "oligo-" in "oligodendroglia" refer to?

a few, each glial cell myelinates a few axons

Conductance to what ion activates late in the action potential?

The late conductance increase is for K+

If multiple sclerosis involves an immune attack on myelin basic protein, and if everybody has this protein in their myelin, how come everybody does not have MS?

rarely does autoimmunity develop

Suppose a cell's resting membrane potential is -60 mV (inside negative). Give a reasonable value for the potential if it received an inhibitory synaptic input causing a graded hyperpolarization.

-65

Explain why propagation of the action potential is unidirectional in terms of the refractory period.

spike cannot triger a spike behind it because that membrane is still not excitable

From the cable equation, we derive properties of the space constant and the time constant. How does that tell us why invertebrates have giant axons?

space constant increases with the square root of the radius

Given that current leaks through capacitors and that membranes have high capacitance, how come myelin, with its many membrane layers does not leak a huge amount of current?

capacitors add reciprocally

For multiple sclerosis, explain autoimmunity (i.e. distinguish it from active immunity against antigens in pathogens).

the antigen is probably a myelin protein

There are cells that look like pseudomonopolar neurons in the dorsal root ganglion (just outside the spinal cord). What function do these cells serve?

sensory input

If you had one size of axon, why would the depolarization 1 mm ahead of a spike be greater with myelin than without (assuming the Schwann cell's myelin is 1 mm long).

Myelin's resistance and capacitance decreases current loss across that distance

What is the toxin from puffer fish that blocks the Na+ channel (and hence the action potential)?

tetrodotoxin

What happens with botulism toxin? (Your answer can be molecular, cellular, or physiological.)

cleave synaptobrevin, block vesicle release, muscles blocked

The conclusion from Loewi's work was that there must be a substance involved. How did his classic experiment show this?

juice from chamber where vagus stimulation slowed heart slows heart in another chamber

Describe the geometry of the input to the spinal cord of the muscle stretch receptor.

cell body is in ganglion as axon goes into dorsal root

If ms (multiple sclerosis) can arise from exposure to myelin basic protein, how come everyone does not have ms?

proteins sequestered from imune surveillance except when there is autoimune disease

Why do they call neurotransmitter vesicles in the process of release "omega figures?

in EM they look like the Greek letter

Ionotropic vs. metatotropic is a way to distinguish neurotransmitter receptors. If muscarinic is metabotropic, what is the corresponding ionotropic receptor for cholinergic transmission?

nicotinic

What is the immediate precursor for dopamine and why is it especially useful as a treatment for patients?

l-DOPA can be given to Parkinson's patients because it crosses the blood brain barrier

What binds to adenylate cyclase to activate so that it makes cAMP out of ATP?

alpha subunit of heterotrimeric G protein

What does protein kinase A (PKA = A kinase) do to the proteins it affects?

phosphorylates them

Once it is activated, what keeps the alpha subunit of the heterotrimeric G protein from running amuck and continuing to activate the next molecule in line in the cascade?

it has GTPase activity then recombines with beta gamma


Where (specifically) is synaptobrevin and what (molecularly) does botulinum toxin do to it?

on vesicle, cleaves (prevents vesicle release)

Reuptake is the predominant mechanism to terminate norepinephrine action. By contrast, how is acetylcholine action ended?

breakdown by AChE

Why might an inhibitor of monamine oxidase (MAO) relieve depression?

potentiate "upper" action of norepinephrine by keeping it around

Why do squids have giant axons? Your answer can be behavioral, it can pertain to the properties of giant axons, or it can be comparative (comparing squid with "higher" nervous systems).

so they can contract their mantle for the escape response synchronously, giant axons conduct faster, invertebrates do not have myelin

Why is salutatory conduction so much faster than conduction without myelin?

all that insulation forces the action potential to jump way ahead to the next node of Ranvier

Why is the prefix "oligo" applicable to olidodendrocytes?

they myelinate several axons in the CNS

"Capacitors in series add reciprocally." What does this say about the capacitance of myelin?

less current would leak out of the axon through the membrane capacitance where there is myelin

By passive spread, a spike at one place depolarizes the axon ahead of it (and behind it) to threshold. Why is conduction unidirectional?

because the sodium channels behind it are inactivated, causing the absolute refractory period

Why might a middle-aged person who had recovered partially from "infantile paralysis" (polio) experience a relapse?

Post polio syndrome has sprouts of motor neurons going away (motor unit goes back to before recovery of function)

An oscilloscope presents the action potential like a graph. What are on the X and Y axes?

X time, Y voltage

Why was Golgi's technique, so exquisitely used by Ramon y Cajal, a contribution worthy of the Nobel Prize?

Among a zillion cells, one cell could be seen in its entirety

Structurally, how are Schwann cells and oligodendrocytes different?
 
Schwann myelinate one axon, og. Do a few (hence oligo-)
 
Molecularly. What does it look like when inactivation of a channel occurs?
 
A stopper plugs up the channel
 
In what way was multiple sclerosis modeled as an autoimmune disease?
 
A basic protein in myelin, usually sequestered from immune surveillance induces immune attack on myelin
 
Tetrodotoxin (from puffer fish) would kill you by what mechanism?
 
Blocks sodium channels and hence the action potential

"Exponential" is the term describing Voltage as a function of time for charging or discharging a capacitor in an RC circuit. Draw this graph (for charging or discharging or both) where V is the battery's Voltage.

charging - goes up quickly then slowly, leveling off to V; discharging - goes down quickly from V then leveling

In contrast with ligand-gated channels like the nicotinic receptor, how is the sodium channel of the action potential gated?

it is voltage gated, charged amino acids on alpha helix detect voltage

Why doesn't an action potential trigger an action potential behind it in the axon?

there is a refractory period caused by sodium channel inactivation

What is different about the space constant vs the time constant for the passive propagation that explains why giant axons are fast?

space constant varies with square root of radius, time constant does not

What happens to the permeabilities of the axon membrane for Na+ and K+ during the passage of the action potential?

permeability of sodium goes up then down, later the permeability for potassium goes up then down

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