Transcribed by Tina Park Neuroscience Lecture 17 Action Potentials II by Dr.

Joel Schiff

Monday, February 3, 2014

Hour 1: Action Potentials II [00:01:26] Dr. Joel Schiff Okay. On Friday, after I described the action potential, I sort of ended with comment, So what? Part of this so what is the subject of the first hour of today. Stop and think for a moment. What exactly is the purpose of a neuron? It does several things. Neurons carry information in the form of action potentials from one place to another. Neurons, as you saw from morphology from Dr. Sanchane presented, can have relatively long axon projections. Basically when you decide up here to wiggle a toe on your right foot, your e talking about two axons making the whole trip with one synapse, or less, between them. So you have these very long projections, the axons are neurons and you want to get the fact that an action potential has been formed. You want to get that information down to the other end of the long axon so that it can signal whatever cell it is going to, perhaps another neuron. It forms a synapse, which I will talk about in the second hour. So what we have got, basically, is a way of getting the information that there is an action potential of an axon to another. Now as Dr. Sanchane pointed out, we have a basic cell body and dendrites, which I am not going to draw, and it has an axon hillock, which leads to an axon. The yes or no, or All or none decision about whether an action potential is going to form in this axon is made at this axon hillock depending on whether the depolarization of that region of membrane reaches a threshold, -55 or so, or not. So if it does you get an action potential. An action potential forms right there. What is an action potential? It is a time sequence of permeability changes, which produces membrane potential changes. As I went through on Friday, first you get an increase in permeability of Na and that leads to a depolarization and that opens more slowly K channels so you get an increase in permeability of K and that leads to repolarization. And there is your action potential. [Increase PNa depolarization increase PK repolarization] So, this is the time sequence of permeability changes and voltage changes that are occurring here. But what about somewhere else in this axon? What happens is Humph. Thats a shame. I was looking for a long extension cord or rope or something. Try it at home. If you have this depolarization. Now what I am drawing here is... This is no longer a time axis. This is a space axis or position axis. And here is your axon hillock, and you get an action potential here. What about some distance x along the axon? When your membrane potential changes in some point along the axon. And remember this is in time. This is going up slowly. And when it reaches -55 it goes up rapidly. And then not quite as rapidly it goes back down. Theres a little period of time where it goes hyperpolarized and then it goes back to the resting potential. Thats your action potential sort of in a different dimension. Thats what happens here. At some time when the membrane potential is depolarized this much here, whats going on some distance away, lets say here? The differences in membrane potential between two places, here and here, set up electrical fields, which drive currents of ions moving through intracellular and extracellular fluid. You end up with phenomena known as electrotonic spread. Electrotonic spread is simply that a depolarization in one place will influence other places on the membrane, or on the axon, near it. So, lets say that at a particular time, this is -70, this goes up to -60. Its on its way up; it just reached -60. What happens? Does that affect this area over here? Yea, sort of. Because the way it works out, the electric field leads to something that is going to depolarize the nearby areas of membrane. But there is an exponential fall off, decay. Not decay with time but with distance. Because if I Consider a rubber band stretched from here to there. If I press down over here, the part over there is going to be pulled down somewhat, not as much as where I pressed it, but somewhat. Same thing if I lift it up. That lift up is going to spread out. And if you work it out for the membrane. I am not going to go through the math because I discovered long ago in my teaching career that as soon as I start writing differential equations, you tune out completely and you never come to the next lecture. So while Ive got you here, lets just say this is an exponential decay. It falls off as e to the minus some function of distance. The question is does it decay fast or slow? Does it stay localized? In other words if you raise this here, does it go down very fast? This kind of exponential, or is it a much more gradual exponential? Does it spread further? The depolarization will spread a certain characteristic distance. And the way in which this distance is expressed is usually in terms of some length constant, Lambda. And you put the X over lambda. So X is measured in

terms of length constant. So if you have a big lambda, then by the time x equals lambda and this and this becomes e to the -1 then you will be way out here. And if you have a small lambda, it will go down very quickly. And so the point is 1 over e of the depolarization might be near by or much further away, depending on the lambda, the length constant, and that is what this distance is. Whether it is over here or out here. Obviously Im being very vague about the lambda because what determines it is what this lambda is, this length constant. It turns out what you want to look at to figure out what determines this lambda is: What is going on in spread in this depolarization? If you have this axon here, here is an axon, in, out, and you depolarize this up to say -60mV from 70, then this is positive compared to out here. This is more positive. The outside becomes a little less positive, less potential difference across this membrane. So whats going to happen is the positive ions that are moving Well they are actually moving in, I should have drawn it with an arrow. Lets change that. I know what to do; well draw at the bottom of the axon. This is depolarized because there is positive ions moving in, Na usually. Moving in. and those Na ions coming in are going to eventually move out, eventually, because everything has to balance out. So what is going on is, you end up with a certain amount of electrical current going into the cell, this current is moving out of the cell, and it also has to travel along the interior of the axon. Now, I think I lost you. Lets try to find you again. Or let you find me. How would you depolarize an axon? You would send an electric current into it to make the inside more positive. So theres a current moving in. Lets say youve got an electrode outside the membrane connected to a battery or a power generator. And you are sending an electric current into the cell. And that makes the inside more positive. So you are depolarizing it. To complete the circuit, you connect this to your power generator. And you connect some other electrodes to the extracellular fluid. And you send the current in and the current has to come back out to complete the circuit, and it crosses the membrane. Now the question is, does this cross the membrane only very close to where it went in, in which case you have very little spread of depolarization, or does it travel a ways before it comes back out of the cell, in which case you have a big spread of depolarization? The answer is this: it depends on the resistance of the membrane because if the membrane has very high resistance, then its going to spread further because it cant get out very close to here. So its going to go further and look for more membrane to go through. So the membrane resistance determines the lambda in that you get a longer lambda with a higher membrane resistance. On the other hand, if you want this current to spread along the axon, theres a certain amount of electrical resistance inside the axon. Its not a wire; its a tube full of ions. So, if this has very high resistance, well call it the longitudinal resistance, the resistance along the axon cytoplasm. If this is very high it will be very hard to spread it further, so well stay more localized. So a high longitudinal resistance will decrease lambda. This will increase it. So it turns out if you do the math and dreaded differential equations, what you end up with is this expression: Lambda is equal to the square root of the membrane resistance over the longitudinal resistance. In other words, if the longitudinal resistance is low, its easier for stuff to spread. So a low longitudinal resistance will make this fraction bigger and you get the bigger lambda. If the membrane resistance is high, then that will essentially confine the electric current to the inside of the cytoplasm and it will spread further. If this membrane resistance is high you get a higher lambda. And if you juggle the units around you get that square root. Now the key to this is why do you care about this length constant or the electrotonic spread at all? Because that determines how fast an action potential will travel along the axon. Because suppose this now reaches -55 and starts to shoot up very fast because at -55 you get the positive feedback, the depolarization opens more Na channels, which give you more depolarization, and the membrane potential zooms up towards positive territory. So lets look at this a tiny amount of time later. Lets say you reached -54mV. This depolarization has spread somewhat, as sort of e to the minus lambda. Right? So as long as this exponential decay exists here, theres a region right around here thats depolarized -55 mV. So this area starts getting positive feedback control, opening more Na channels, this goes up, and when this gets to -54, or -54.9 or whatever, it will spread further and cause an action potential to form here. And this will get up here and cause an action potential to be formed somewhere here. Now it should be fairly clear, I hope it is, that if you have a very large lambda, so that when this is -55when you reach -54 with a large lambda, this will spread further and you end up with an action potential being formed over a longer range of distance. Where as in the time it takes to reach -54, if you have a smaller lambda, itll only have spread a

smaller distance. So this speed at which the action potential travels along the axon depends on the length constant. So the velocity is proportional to the length constant , which is equal to the square root of resistances. Why is any of this relevant? Well suppose you have two axons that are going from one place to another. And here is one, just show a cylindrical section, and here is another. The membrane resistance will be smaller if you have more membrane. Just as if you have a larger area of a strainer, or a filter paper, more liquid can get through. If you increase the surface area of membrane, then the overall permeability of ions to get through because there are more channels to get through if you have more membrane. So the membrane resistance, here, is going to depend on, lets say proportional to, let me get rid of this. The membrane resistance is going to be inversely proportional to the area around the axon. Its bigger for this axon and for this one. Surface area. But the surface area really corresponds to the circumference of the circle, equals pi times diameter or two pi r, that you learned ages ago. The membrane resistance is smaller for a larger circumference, which is 1 over C, which makes it one over pi times diameter. You learn this in terms of radius but what people tend to measure in terms of an axon, and this goes back to all those histologists my apologies Dr. Wishe, is that they look at a cross section and the easiest thing to measure is the diameter. So the histo- people look at diameters, the mathematical physiologists tend to look at radii because we dont have to sit down at a microscope and measure them, we can just talk about them. So one over pi times diameter. Another thing is how far this spreads along the axon here this way. Depends on the cross sectional area of the axon, because the more surface area, the easier for ions to travel along it. You got more water down a wide hose than a narrow hose. If you have an electric circuit and you have a thick copper wire versus a thin strand of copper you can get more current down the thick one that the thin one. So here the longitudinal resistance here is proportional to one over the cross sectional area of the axon. Now the area of the axon is one over pi r squared. Right? Thats the area of this circle, which is, if you multiply both sides by four you get four over pi diameter squared Okay. So lets look at the speed of the axon potential. Its proportional to the length constant depends on and is square root of RL. The membrane potential depends on/is proportional to one over diameter lets forget the pi for a moment. The longitudinal resistance depends on the cross sectional area, which depends on one over diameter squared. So the length constant depends on one over diameter divided by one over diameter square, you divide fractions by inverting the other one and multiplying and you end up with square root of diameter. Whats the point of all this? I dont want you to remember all this whole derivations. What I do want you to remember is this last conclusion. The speed at which an action potential travels along an axon is proportional to the square root of that diameter. So the whole idea is that if an animal wants to develop a long pathway it would have to develop a large diameter axon to get the information from one end to the other in a reasonable amount of time. You want a faster conduction speed, and therefore since conduction speed goes as the square root of the diameter, you would have to make bigger and bigger diameters. But theres another factor that happened with the development of us. By us Im including vertebrates in general. We have vertebrata, chordata have a spinal cord. You take a lot of these axons going form one end to another and put them into this tube. If youve got big fat axons you cant get that many into a small tube. And we have hundred thousands millions of axons running along our spinal cord so we cant make each axons very big or else we would have spinal cords the size of tree trunks. Which might have problems. So around the time we developed as vertebrates we also developed myelination, which Dr. Sanchene also described to you Schwann cells wrapping around, multiple layers, so on and so forth. The key to that is when you have a myelinated axon compared to a comparable sized unmyelinated axon, first of all this relationship of square root of diameter, velocity proportional to square root of diameter, no longer applies. Purely and empirically it was found about 80 years ago that the velocity in a myelinated axon is actually proportional to the diameter, not to the square root of the diameter. So if you get a bigger and bigger axons, instead of the velocity going up as a square root, this sort of parabola on the side, the velocity goes up proportional to the diameter and you get much higher velocity for a given diameter of an axon. So this enables us to get relatively rapid conduction by virtue of myelinating an axon. Now whats really going on when you myelinate an axon? All sorts of cables over here I dont know what they do. But since I dont use PowerPoints, I dont care if I mess things up for

other people. You have to keep in mind when an action potential is traveling along an axon that its not moving along an axon. Nothing is moving in a longitudinal direction. See what happens is, if an axon potential appears on one place on an axon that depolarizes the next part of the axon which then goes through an action potential which depolarizes the next part and so on. So you end up with this wave moving along this axon, appears to be moving. But heres the key to it all, if you keep youre eye on one particular spot on the axon, I made a knot. Real axons dont have knots you should hope that yours dont. The knot doesnt move, it just moves up and down, just as this moved up and down. Nothing actually moves. The movement or propagation is an illusion really that depends on the fact that each section of an axon depolarizes to the critical threshold of -55 mV. This is referred to as liminal depolarization. The depolarization that doesnt reach -55 is subliminal depolarization. The point is that an action potential triggers and action potential here except not in secrete steps but its just moving along. What happens in a myelinated axon that gets you this faster conduction speed? Theres two ways of looking at it. One is if you have an axon and you cover this internode with schwann cell membrane, leaving nodes of Ranvier exposed in between, where can there be an action potential? Well define action potential? I feel like President Clinton when he was faced with an impeachment movement trying to disguise what having sex means. What you have here is, what do you mean by action potential? And as I described earlier, an action potential is an orderly sequence of permeability changes. Each of these permeability changes first the increase in permeability of Na, then increase in permeability of K. Each permeability change leads to ion movements. So the point is in the internodes where you have Schwann cells wrapped around, you have an action potential there. The answer is no by that definition. Because when you dont have an action potential there, you dont have permeability changes because Schwann cell is blocking all of the ion channels in axon membrane. There is no way Na and K ions can get through this whole wrap up of internode. So basically you cant have action in internodes but you can have an action potential on nodes of ranvier, here, here, and son on. So what appears to be happening is that if you have an action potential here it leads to an action potential here and so on. And the action potential appears if you are trying to measure it to be jumping from one node of ranvier to the next. This jumping is usually referred to as salutatory conduction. And it has nothing to do with salt. Saltare means to jump. Which leads to the French word saut you put in and toss it around. Ls and Us get switched around in French. What happens here is jumping from one node to another. Okay how does that lead to faster conduction? The answer to that is, there are two ways of looking at that. One is what slows down action potential conduction is that theres an enormous amount of membrane being exposed on an unmyelinated axon. Youre basically using the whole surface of the axon so the unmyelinated axon has a larger surface area per length than the myelinated axon. And with larger surface area has larger capacitance and therefore is lower time constant. So the action potential to go through whole steps of depolarize and repolarize and so on does it a little more slowly and propagation of action potential is slower. Another way of looking at it is this, the speed is proportional to the square root of membrane resistant divided for longitudinal distance even for myelinated axon. What does membrane resistance of myelinated axon look like? Well if you take sort of, um, subunit here divide into equal subunits consisting of one node and one internode, or half a node plus an internode or something like that. On average 9o% or so is wrapped up with insulator, the Schwann cell membrane. So the average membrane resistance on a myelinated axon is very high. And the reason its very high is that a lot of the axon, the parts that correspond to the internodes, have effectively infinitely high resistance. Ions cant get in and out during the internodes. So when you average in a small area that does allow ions to move, on average the membrane resistance is much higher. And that will lead to a longer lambda and faster action potential propagation speed. Okie dokie. So either way you look at it what are basically happening is by having this salutatory conduction, you can get a larger conduction speed in an axon of a given size. Now so much for action potentials. Uh. Hm. Do you want to take a break now or do you want me to keep going and finish early? You want to take a break. Take ten, but be back. [00:48:00]