Chapter 5: The Nerve Impulse
What you need to know

(exam questions will be a drawn from this subset of material)

What's the difference between a nerve impulse and an action potential(p. 109)
nothing; they are different names for the same thing

What do the terms depolarization and hyperpolarization mean?  (p. 109-110)
Saying that the membrane potential gets "larger" or "smaller" is ambiguous;
For example, -30 is larger than -60 in the algebraic sense, but  is smaller in magnitude (i.e., absolute value).
To avoid this ambiguity, neurophysiologists use:
depolarization to refer to a change that makes the inside of the cell more positive
hyperpolarization  for a change that makes the inside of the cell more negative
For example, a change from -60 to -30 mV is depolarizing and a change from -30 to -60 mV is hyperpolarizing.

What are typical values for the amplitude and duration of an action potential?  (p. 109)
on the order of 100 mV in amplitude and about 1 msec in duration

Why is an action potential said to be all-or-none (p. 110, 115)
Because the amplitude of the action potential is independent of the magnitude of stimulus that elicited  it.
Action potentials do not come in different sizes;  you either get a full sized AP, or none at all.
(in reality there are several caveats to this statement, but this is the key concept)

What is the key biophysical mechanism that underlies the generation of an action potential?  (p. 110)
voltage-dependent changes in the permeability (conductance) of Na+ and K+ channels in the cell membrane

Outline the sequence of conductance changes that takes place for Na + and K+ channels during an AP?  (p. 116)
1) initial depolarization (due to synaptic input from other neurons or current injection by the experimenter);
2) leads to an increase in conductance of voltage-dependent Na + channels (upstroke of the AP);
3) followed by an increase in conductance of voltage-dependent  K+ channels and  inactivation of Na+ channels (down stroke)
4) followed by a decrease in  K+ conductance back to resting levels (repolarization)

Outline the sequence of ionic currents (Na+ and K+ ) that flow during the different stages of the AP?  (p. 116)
1) a sharp increase in inward Na+ current (upstroke of the AP);
2) a delayed increase in outward  K+ current (due to K+ channel activation)
3) a decrease in inward Na+  (due to Na+ channel inactivation)
4) a decrease in outward  K+ current back toward resting levels (repolarization)

What role does positive feedback play in the generation of the AP?  (p. 116)
Positive feedback causes an extremely sharp rise in the Na+ current at the beginning of the AP:
1) an initial depolarizing stimulus causes an increase in the fraction of v-dep Na+ channels that are open,
2) opening of Na+ channels causes more current to enter, further depolarizing the cell
3) further depolarization causes  more v-dep Na+ to open
4) GO TO STEP 2

(Positive feedback is also responsible for the shriek of a public address system that occurs,
for example, when a microphone  is placed  too close to a  loudspeaker.)

What's the functional role of sodium inactivation(p. 117)
it stops the influx of Na+ ions and allows the cell membrane potential to recover

Do potassium channels inactivate, just like sodium channels?  (p. 117)
Some types of K+ channels do, but not the ones associated with the repolarization of the AP.
So for understanding AP biophysics, remember that Na+ channels  inactivate but K+ channels don't.

If you poison a neuron with a metabolic inhibitor that stops operation of the Na-K pump, can the neuron still generate APs?  (p. 117)
Yes, it can continue to generate APs for many minutes.
The ability to generate APs depends only on passive factors (concentration
and electrical gradients), not active transport.
Eventually the neuron will lose the ability the generate APs because the concentration gradients will collapse without the Na-K pump.

When Na+ ions rush into a neuron during an AP, is the intracellular concentration of Na+ changed significantly?  (p. 117-118)
no, the change in concentration is negligible under most conditions

What happens to the size of an AP if you increase the external Na+ concentration?  (p. 118-119)
the peak amplitude of the AP increases

Who were Hodgkin and Huxley?  (p. 119-122)
Hodgkin and Huxley were two British electrophysiologists who did voltage clamp experiments on the squid giant axon in the 1940s and 1950s.   Based on this experimental work they developed a mathematical model of how  Na+ and K+ conductances depend on voltage and time.  In 1952, they published a key paper with a full quantitative model for the ionic basis of the action potential in squid axon. The Hodgkin-Huxley model is still in use today.  Hodgkin and Huxley were awarded the Nobel Prize for their work in 1963.
What is a voltage clamp?  (p. 119-122)
A voltage clamp is a way of electronically controlling the membrane voltage to hold ("clamp") it at a particular value chosen by the experimenter.
The membrane voltage remains constant, even though there can be  ionic currents flowing through open ion channels in the membrane.
Using a fast feedback mechanism, the voltage clamp circuit  generates a "clamp current" that counters the  ionic currents.
By monitoring the clamp current, the experimenter can measure the ionic currents that are flowing across the membrane.

Draw the clamp current that might be seen in a squid axon when the clamp voltage is stepped from -60 mV to 0 mV.  (p. 119)
See Fig. 5-5 A

What would the clamp current look like in the above experiment  if Na+ channels were blocked? if K+ channels were blocked? (p. 119)
See Fig. 5-5 B

What would the clamp current look like in the above experiment if the external [Na+] were reduced to match the internal [Na+]?  (p. 121)
In the internal and external concentrations are equal,  the  Na+ equilibrium potential would be zero.
In a voltage clamp experiment with a clamp voltage of 0 mV, no Na+ current would flow.
Thus the clamp current would be the same as if the Na channels were blocked.
See the curve labeled IK in Fig. 5-5 B.

Draw the time course of changes in Na+ and K+ conductance during an action potential?  (p. 122)
See Fig. 5-6

Is there a particular voltage where the ionic conductance changes sign?  (p. 122)
No, conductances are always positive; they never change sign.
Ionic currents can change sign and membrane voltages can change sign, but conductances are always positive.

Who are Neher and Sakmann?  (p. 122)
Two German electrophyiologists who developed the patch clamp technique in the mid 1970s  for recording the incredibly small currents that flow through individual  ion channels. Neher and Sakmann used this technique to determine which parts of the molecule constitute the "voltage sensor" and the interior wall of the channel, and how the channel regulates the passage of positively or negatively charged ions. They shared the Nobel prize in 1991 for this work.
What is a patch clamp?  (p. 122-124)
A patch clamp is a way of carrying out a voltage clamp experiment on a tiny patch of membrane containing only one or a few ion channels.
The technique involves sealing a fine-tipped glass micropipette to a small patch of  membrane, typically a few microns in diameter.
It also requires special low-noise electronics for accurately measuring the very small (picoamp) currents.

Does an individual ionic channel show a continuous range of conductance states?  (p. 122-124)
No, individual channels are typically either open or closed.
Some types of ion channels can have more than one open state, but these conductance states are always discrete, not continuous.
Individual channels flicker ON and OFF.

What are the two main functional types of "gates" in voltage-gated ion channels?  (p. 124-125)
activation gates - open when the membrane depolarizes, allowing current to flow through the channel
inactivation gates - close when the membrane depolarizes, blocking current flow through the channel
The Na+ channel displays both activation and inactivation gating properties, while the K+ channel displays only activation gating.

What is the refractory period of a neuron?  (p. 125)
The refractory period is the period of time following an AP when it is more difficult to excite the neuron to fire another AP.

What is the difference between the absolute and the relative refractory period?  (p. 125)
During the absolute refractory period (typically about 1 msec) it is impossible to fire another AP, no matter how strongly the neuron is stimulated.
During the relative refractory period (typically several msec), another AP can be elicited if the stimulus is sufficiently strong.

What is the biophysical basis of the refractory period?  (p. 125)
The absolute refractory period is primarily associated with Na+ channel inactivation.
The relative refractory period
is associated with both  residual Na+ inactivation as well as increased K+ conductance following each AP

Are Na+ and K+ channels associated with the AP the only kinds of voltage-gated channels that are found in neurons?  (p. 126-128)
No, a single neuron often contains many different types of voltage-gated channels.
More than 50 different types of voltage-gated potassium channels have been described (although not all in one neuron!)
The particular combination, density, and distribution of channels gives each type of neuron a unique "electrical personality."

How does the AP propagate down an axon?  (p. 129)
Current entering the axon at the site of the AP flows laterally and depolarizes neighboring segments of the axon membrane.
This causes neighboring segments to locally generate an AP, which then depolarizes neighboring segments...
Thus the AP is continually being regenerated as it propagates.

Why doesn't the AP propagate back in the direction from which it came?  (p. 129)
The membrane "behind" the AP is in a refractory state and can't support the generation of a new AP.
The membrane "ahead" of the AP hasn't been activated yet, so it can support an AP.

What direction to APs usually propagate?  (p. 130)
For vertebrate neurons, the spike initiation zone is at the soma and APs propagate away from the soma.
For invertebrate neurons the situation is complicated; their neurites can contain multiple spike initiation zones (SIZ);
APs propagate away from the SIZ, toward the terminal arbor.

What would happen if you initiated an AP by stimulating the terminal arbor of an axon?  (p. 130)
Because the axon membrane is not refractory, the AP would propagate back toward the soma.
This fact is used by neurophysiologists to map functional connections between different brain regions.
While recording from a neuron in brain region A, they stimulate axon terminals in brain region B;
if neuron A projects to region B, a so-called "antidromic" spike can be recorded in neuron A.

What would happen if you initiated an AP in the middle of an axon, halfway down its length?  (not in text)
Because the axon membrane is not refractory, APs would propagate in both directions.

What would happen if you simultaneously initiated an AP at the soma and at the terminal arbor of the same axon?  (not in text)
The two APs would propagate toward each other, but they would be disappear when they collided because the membrane
on both sides of the collision point would be refractory.

In an unmyelinated axon, do APs propagate faster in larger diameter or smaller diameter axons?  (p. 130)
The larger the axon, the faster the conduction velocity.

What is a typical AP propagation velocity in unmyelinated axons ? (p. 130-131)
Unmyelinated: about 1 m/s for small axons (~ 1 micron)  up to about 25 m/s for "giant axons" (several hundred microns).

What does myelin do? (p. 130-131)
It increases AP propagation velocity.

What are nodes of Ranvier ? (p. 131)
Small gaps in the myelin sheath. APs jump from one node to the next..

What is saltatory conduction ? (p. 131)
Saltatory conduction (Latin: saltare, to leap) refers to the AP jumping from one node to the next in a myelinated axon.

Why can APs propagate faster in myelinated axons?  (p. 130-131)
Depolarization can spread quickly from one node of Ranvier to the next because:
myelin lowers the membrane capacitance, thus less charge is needed to depolarize adjacent regions to threshold.
myelin increases the membrane resistance in regions between the nodes, thus less charge leaks out between nodes.
sodium channels are more highly concentrated at the nodes, decreasing the AP threshold..