Understanding Neuron Communication and Synapses

We're going to finish up our description of how neurons work by talking about how one neuron communicates with another neuron and how that target neuron deals with the information that it's been sent. Before we do it, we'll get some terminology out of the way. When one neuron communicates with another, we call the whole structure the synapse. Usually this sort of refers to both the axon and axon terminal of the cell that's sending the information and then The receiving end of the target neuron, it's often a dendrites or the soma, but not always, as we will see. The neuron that's sending the information, we call the presynaptic neuron. And the neuron that's getting the information, we call the postsynaptic neuron. There's nothing special about presynaptic and postsynaptic. This neuron right here that's sending the information, it's got its own soma and dendrites way back wherever they are. So it's also a postsynaptic neuron. So this is all relative terminology. A cell isn't presynaptic or postsynaptic inherently. But when we're just looking at two cells combining at a synapse, we'll call one the presynaptic and the other the postsynaptic. All right. Now, in general, there are two types of synapses. One that tends to be more rare is what's called an electrical synapse. At an electrical synapse. an action potential or a change in voltage in the presynaptic cell actually flows from one cell to the other and causes a similar change in membrane potential, could be an action potential, in the postsynaptic cell. The electricity, as you can see in this diagram, is just transferred from one to the other. The other kind of synapse, the one that is vastly, vastly more common, is a chemical synapse. And that's where a neuron releases a chemical signal, neurotransmitters that bind to receptors on the postsynaptic cell. So we'll talk about these in more detail here. Connecting two neurons at an electrical synapse are gap junctions, places that the cell membranes are kind of fused together by these transmembrane proteins. These gap junctions basically allow ions to flow through. And of course, since ions carry the current that causes the membrane potential changes in neurons, this allows the electricity essentially to flow between neurons. And so here's an example of an electrical synapse where if I inject current into the presynaptic neuron here, this is in the crayfish. I'll get an action potential in that axon. I'm bringing it up to threshold. There is another axon that is connected electrically to this one. And if I measure the membrane potential in that, I see that very shortly afterwards, in fact, within a fraction of a millisecond, I get an action potential in that second neuron, in the postsynaptic neuron. So we see that electrical signaling is extremely fast. The membrane potential change here in action potential is transmitted from one cell to the other in a fraction of a millisecond. So what does this mean? It means that electrical synapses are very high fidelity, meaning that a change in one is pretty much directly going to cause a direct change in the other. And it's very, very, very rapid, but it's relatively rigid, right? And so you only get the one response. It's really great under certain circumstances. Two things that make it really, really useful, and we see them often combined, is of course when you need a really fast response. And so what we see here in this crayfish, if you poke the tail of a crayfish, it will do what is called a tail flip response, where it will contract its very strong tail muscles in response to the... poke as if maybe a predator was trying to eat it. And that tail flip pushes the animal away from danger. And it's got to be really, really fast because it's an escape reflex. And also, when you need, and again, this is sort of combined with fast, but fast coordination, this muscular activity, this contraction of its big, thick tail muscle has to be both fast and coordinated so that the animal is pushed properly and that you get maximal force. And so again, tending to be found in the animal kingdom where you need things that are really fast and really coordinated. In particular, we find them at places where animals have need for really fast reflexes. Okay, that's all we're going to say about electrical synapses. They tend to be relatively rare. We have some in mammals, but not a ton. And most of the synapses that we are going to be talking about in this class and the most of the synapses that we have in our nervous system are of the chemical type. The chemical type where the presynaptic neuron will release a chemical called a neurotransmitter, and it will bind to receptors on the target neuron and cause interesting things to happen. Okay, so what we're going to do now is we are going to give a quick overview of the process of neurocommunication at a chemical synapse. And then we're just going to keep going into more and more detail. We're going to go into detail of a classic chemical synapse, which is actually found between neurons and the muscle. Then we'll look at some more specific types of synapses within the central nervous system. And then we'll talk about the details of what different kinds of neurotransmitters do. But we'll start with the basic process of chemical transmission. And it starts here with a synapse at rest. meaning that there are no chemical signaling between the neurons and no electrical activity in the presynaptic or postsynaptic neuron here. And what we see is that at rest in an axon terminal, we have these balls, these vesicles, these spheres whose envelopes are made up of cell membrane phospholipid type material. And inside them are packaged neurotransmitters. We call those synaptic vesicles. And they're just hanging out inside the axon terminal, waiting to be released. Now, what is the signal for the release of neurotransmitters? It's the action potential. So the action potential has two jobs. Its first job is to travel whatever distance the axon is, right? It's to get the signal from the soma out to the target. And that axon can be really long. It can be going from your spinal cord to your fingertip. It can be going from your toe to your brainstem. It can be going from one side of your brain to another, or it could be just a few microns from nearby cells. But its job is to carry that information from one place to the other. But when it gets to the axon terminal, it has one last job. And that last job is to, of course, do what it does, which is increase the membrane potential in the axon terminal. When that happens, it activates this special class of calcium channels. These calcium channels are voltage gated. And so at resting potential, these voltage gated calcium channels are closed. But when the action potential comes in and raises the membrane potential, the voltage gated calcium channels open. Now, if you remember your cell biology, calcium levels are kept very, very low inside most cells, and neurons are no exception. Calcium, the presence of calcium, normally means that something interesting inside the cell is going to happen, and we'll see this in many cases in this class. But here at the axon terminal, the presence of calcium causes these vesicles to dock with the cell membrane at the docking zone. And when they dock with the cell membrane, they fuse. The vesicles and the contents undergo exocytosis, which releases the neurotransmitter into the synaptic cleft, the tiny space between the two neurons. Exaggerated in distance here. So small that you can't even really see the distance without an electron microscope. Okay. So the voltage-gated calcium channels, which are normally closed, will open as the action potential, driven by the influx of sodium through voltage-gated sodium channels, raises the membrane potential above the threshold for opening voltage-gated calcium channels. Calcium being really, really highly concentrated outside the cell and not very concentrated inside the cell, now comes into the cell down its electrochemical gradient. That calcium causes the docking of the vesicles. probably learned about it in cell bio. We're not going to go through the details in this class. Okay, the neurotransmitter, once in the synaptic cleft, is going to just diffuse. And because the distance is so small, it doesn't take very long for it to diffuse across the synaptic cleft where it binds to receptors on the postsynaptic cell. The binding of the neurotransmitters to these receptors is going to cause some change to occur in the postsynaptic cell. And I'm being deliberately vague about that because we'll talk about the different kinds of change that can occur in a minute. Now, we don't want those neurotransmitters to continually be activating their receptors. We need some method of sort of stopping the signal from coming. There are a number of ways in which the transmitter is removed from the synaptic cleft, and we'll go through the details later. But sometimes it's brought back into the presynaptic terminal. Sometimes there are enzymes that will chop it up. So there are a number of different ways in which the neurotransmitter is removed. But those are the general steps. The action potential causes calcium to come in. Calcium causes the vesicles to be released, the neurotransmitters to be released. Neurotransmitters bind to postsynaptic receptors, which will cause a change in the postsynaptic cell. And then those neurotransmitters are in many ways removed, ending the process. Okay, let's take a look at the... two major things that can happen when a neurotransmitter binds to a postsynaptic receptor. There are two classes of receptor, each one giving rise to a different kind of transmission. The first kind of transmission we're going to talk about is called fast transmission. In this case, the receptors that the neurotransmitters bind to are also themselves ion channels. So this is a dual purpose protein structure. It is one, a receptor, and two, an ion channel. It is both. And so we have a couple of different names for this, depending on whether we were referring to it as a receptor or an ion channel. we can call it, since we'll talk about it as a receptor, it is ionotropic receptor, meaning it moves ions. So sometimes you will hear these things referred to as ionotropic receptors, but they're also ion channels, right? And so let's give them their ion channel name using the Framework that we talked about before, these guys are ligand-gated channels. What opens and closes them? The binding of a ligand. In this case, the ligands are neurotransmitters. And so they have a binding site. They have a pore region. And they will be open or closed, depending on whether the ligand, the neurotransmitter, is bound. So they have two names. We'll use both of them depending on kind of how we're talking about them. But in fast transmission, neurotransmitters bind to ligand-gated ion channels or ionotropic receptors. Now, what happens when a neurotransmitter binds to one of these? When that happens, the ion channels open. And what happens when ion channels open? Ions flow across the membrane. What happens when ions flow across the membrane? The membrane potential changes depending on which ions are actually flowing. And so the result of fast neural transmission is a change in membrane potential that we call a post... synaptic potential. And thinking back to my description of how the nervous system works in general, right? We talked about a short-lived transient change in membrane potential that decays as it goes. That is what we're talking about here. That is a postsynaptic potential that came about because of the binding of the neurotransmitters. the opening of those ion channels. the flowing of the ions across the membrane, bringing their charge with them or taking their charge away, which will change the membrane potential. Now there are two major kinds of postsynaptic potential. There are excitatory postsynaptic potentials, which we abbreviate EPSP, excitatory postsynaptic potential. These are defined as bringing the neuron closer to its threshold, making it more likely that the cell is going to fire an action potential. Right? Vm, normally at rest, is down here, but threshold is up here. If I bring the cell closer with my EPSP, it is now excited. It's getting closer to being an action potential. And so excitatory postsynaptic potentials tend to be depolarizing. The other kind is called inhibitory postsynaptic potential or IPSP. Often, but not always, as we'll talk about later, they are a hyperpolarization of the membrane potential. making the cell harder, making it harder for the cell to generate an action potential. So less chance of an action potential. You notice I didn't say it brought it closer to threshold because in some cases they do, but they make it harder for the cell to generate an action potential. It inhibits the neuron, making it less likely to send its own signals, less likely to be active. Now, as we mentioned, Neurons take all of these postsynaptic potentials, and if they come in kind of at the same time, right at the axon hillock, they get summed together. And if that summation of all the incoming postsynaptic potentials reaches threshold, you get action potentials. Here's an example of an inhibitory IPSP combining with an EPSP, and it kind of causes the two to cancel each other out. And so neurons... integrate information. And again, here's just another description, right? We have IPSP inhibits the EPSPs that you'd normally get from all these inputs that would normally cause action potentials. IPSP makes the cell less likely to fire an action potential. So the neuron sums all those up and generates its output as a result. So that's fast neurotransmission in a nutshell. Neurotransmitters bind to the binding sites of the ionotropic receptors or the ligand-gated channels, if you want to call them that. That causes them to open ions across the membrane. Imagine that if you open a sodium channel, sodium is going to come into the cell and raise the voltage, right? Imagine that you open a potassium channel. Potassium is going to want to leave the cell and it's going to cause the voltage to go down. That would probably be an IPSP. All right. What about slow neural transmission? Slow neural transmission also involves the binding of neurotransmitters to their receptors. But in this case, those receptors are not themselves ion channels. In fact, we call them metabotropic. receptors. Metabotropic kind of means you're mobilizing chemical pathways. What happens when neurotransmitters bind to a metabotropic receptor is slow transmission. And typically what happens is that these receptors, not being ion channels, are going to activate some kind of other set of things that are going on in the cell. Second messenger systems, many of them are G protein coupled, meaning that... When the neurotransmitter binds, you activate the G protein complex, which could do all sorts of other interesting things within the cell. In some cases, the G protein complex can open ion channels directly or even close ion channels directly. In other cases, the G protein complex is set off all sorts of interesting and diverse sets of processes within the cell. that can do all sorts of interesting things to the cell's properties, kind of like fooling with the cell's settings. So it doesn't directly change the membrane potential sort of immediately, but as we will see. There are all sorts of subtle things that you can do to a cell to change its properties. And we'll go into more detail about both fast and slow transmission when we look at specific examples. So quick overview, just reminding us how the nervous system works. Let's take a look at a transmission of information between one cell and another. Let's say this cell here is generating action potentials, which are... all or nothing impulses, right? They are the same height, the whole way along the length of the axon. At the axon terminal, they're going to cause the release of neurotransmitters from this cell here onto its target cell, the presynaptic or the postsynaptic cell. In fast neurotransmission, that release of neurotransmitter and its binding to the ionotropic receptors is going to cause a postsynaptic potential. We call it graded because if you release a lot of neurotransmitter, you'll get a high EPSP, right? Let's say I have three action potentials coming in. I'll actually release a lot of neurotransmitter. I'll get a big EPSP. If I only have one action potential, I might get a smaller one. And so that EPSP can be different sizes depending on how much neurotransmitter is released. That EPSP is going to travel to the axon hillock. It's actually going to... K as it travels. It's not constantly refreshed by opening voltage-gated channels like you have in the axon. And then at the axon hillock, all of the different voltages that are coming in from all the different dendrites in the soma are going to be summed up. And then this neuron will decide whether to generate action potentials or not. And that'll just continue to bounce around your nervous system until ultimately you'll get to the muscles. right? The output of your nervous system is to control your muscles. And that brings us to our first example, synapse. Sort of the simplest and the most well-studied and a good place to sort of take a look at some of the very specifics of neurotransmission. It's the place where your motor neurons, most of which live in your spine, whose cell bodies live in your spinal cord. They send their axons out to your skeletal muscles where they cause a contraction. This is called the neuromuscular junction. It is the junction between the axon and the axon terminal of your motor neurons and your muscle fibers, these parallel pink structures. And so you can see here, here's one axon that actually activates many, many individual muscle fibers. It's called a motor unit. We'll talk about that later in class. Here's a cool electron micrograph of it where you can see the axon terminal here. And then underneath it is the place where you would call it the postsynaptic cell. Here we call it in the muscle fiber, we call it the end plate. All right. So let's take a look at this system. At your neuromuscular junction. You have the axon terminal as we described it before. You have vesicles. In this case, they are filled with the neurotransmitter acetylcholine. Typically, every neuron will release one type of neurotransmitter. There are exceptions, but normally in terms of like fast neural transmission, there is one type of neurotransmitter that it releases at all of its axon terminals, right? So even though it's branching into multiple places, it's releasing the same neurotransmitter at all of them. And this is kind of a universal feature of neurons. Obviously there are exceptions, but motor neurons that activate your muscles release acetylcholine, the neurotransmitter acetylcholine, often abbreviated ACH. So the vesicles are filled with acetylcholine. There are voltage-gated calcium channels and voltage-gated sodium and potassium channels for making an action potential. When the action potential gets there, it opens the voltage-gated calcium channels and causes calcium to come in, causes the vesicles to dock, which causes the acetylcholine to be released into the synaptic cleft, or in this case, the neuromuscular junction. Now, on the muscle fiber, you have receptors and these receptors are really, really dense at the neuromuscular junction. In fact, the neuromuscular junction, the end plate is folded, um, with a zigzag sort of motif, uh, which gives more surface area for having more receptors. Um, Your nervous system and muscular system really, really wants this to be a really powerful synapse so that a single release of neurotransmitter from the motor neuron is going to cause a definitive response in the muscle fiber. If you take physiology, you'll find that that response in the muscle fiber is actually an action potential. But you want to depolarize this muscle fiber reliably. You don't want... You don't want, at least in the vertebrate nervous system, to integrate information at your muscles. Okay, so there are lots of acetylcholine receptors, and they have, of course, binding sites for the neurotransmitter acetylcholine. Acetylcholine is released into the synaptic cleft of the neuromuscular junction. When acetylcholine binds to this receptor, it opens its pore. right? This receptor is also an ion channel. It's an ionotropic receptor or a ligand-gated ion channel. When that happens, now ions can flow through. Now you will notice that in this diagram that this channel is actually permeable to both sodium and potassium. It is a cation channel. It allows positively charged ions through mostly monovalent. cations like sodium and potassium. So what does that mean for your muscle cell or a neuron that has acetylcholine receptors in them? What's going to happen? Is more sodium going to come in or is more potassium going to leave? How is this going to change the membrane potential if positive ions are going in both directions? Well, we can study this by making an IV curve. We can hold the voltage of a cell at a particular... membrane potential. We can then release acetylcholine onto the cell and measure the current that we get as a response. And what we see is that, and here remember, negative current is inward, right? Meaning that this is in and this is out, that positive ions are coming into the cell, right? And so inward current is going to depolarize my cell if I wasn't clamping my voltage. And so what we see is that at normal resting potentials, there is an inward current, which means that more sodium is coming in through this channel than potassium is leaving. What happens if we clamp the voltage more and more positive? membrane potentials or even no membrane potential or even positive membrane potentials that we see that there's a relatively linear IV curve that goes from inward to outward current at around zero millivolts and then above zero millivolts you actually get a net flow of ions, positive ions, out of the cell, right? Remember upward here is outward current which will tend to hyperpolarized the cell. Why is this? Well, it turns out that where this line crosses zero, right, where there is zero current, we call that the reversal potential, right? It's the membrane potential where you get no net current. Tends to be, or is, the average of the equilibrium potentials of the ions that this channel is permeable to. But it's weighted by how permeable the channel is to those ions. It's actually very similar to finding the resting membrane potential using the Goldman equation or thinking about the flow of ions at rest. Right. It turns out that the in a neuron, the equilibrium potential of sodium is around 50, 55. millivolts and equilibrium potential of potassium is around minus 100. And it turns out that the reversal potential of these channels tends to be around zero. It's kind of a coincidence that it happens to be around zero. There's nothing special about the number zero here. But if we think about it, it's actually fairly straightforward. At zero millivolts, The driving force on potassium is about twice the driving force on sodium, right? You're twice as far away from... potassium's equilibrium potential as you are from sodiums. Minus 100 here, right? You're really, really, really not negative enough to keep potassium from leaving. You're also not positive enough to stop sodium from coming in, but sodium is only about half the driving force, right? 50 versus 100 millivolts. Well, it also turns out that the channel itself is about twice as permeable to sodium as it is to potassium. And so you have twice the driving force for potassium, but half the permeability. And so at zero, which is where you have about twice the driving force for potassium, is where you'll end up with no net flow. And so you can generate an IV curve here. And here where the line crosses zero, that's not an equilibrium potential. The equilibrium potentials are minus 100. plus 50 of an ion. But for this channel, the reversal potential happens to be, in this case, around zero. Okay. Now, what actually happens at the muscle fiber as a response to the release of acetylcholine is that because the... current is inward because sodium comes into the cell, you end up with a postsynaptic potential that we actually call the end plate potential, just because we need to have a different name for it in a muscle. It looks just like an EPSB, right? The VM goes up closer to threshold. It turns out that in a muscle fiber, here's your end plate, it's actually in the middle of the fiber. Immediately surrounding the end plate are voltage-gated sodium and voltage-gated potassium channels. The muscle fiber is actually just like an axon. And as soon as you depolarize the area around the end plate, you immediately get an action potential that zips away from the neuromuscular junction in opposite directions being carried. and propagated by the voltage-gated sodium and potassium channels that line the cell membrane of a muscle fiber. If you're interested in learning what a muscle fiber does and how it works, you can take physiology. All right, so that is neurotransmission at sort of a real simple synapse. We actually call it neuromuscular junction. It's got relatively straightforward receptors. There's one type of receptor, what we call the nicotinic acetylcholine receptor, called nicotinic because it binds nicotine. There are other types of acetylcholine receptors that work in different ways that we will talk about later in the class. Let's move to the central nervous system. Let's now talk about the major classes of the nervous system. synapses that we find in the brain and in the spinal cord. They tend to be a little bit more complicated, but they work on the same principles. And first, we're going to talk about the major excitatory central synapses. So these are going to be the major excitatory synapses that are one neuron excites another neuron, causes an excitatory postsynaptic potential in it, brings its voltage up higher, closer to threshold. The neurotransmitter that is released at central, meaning brain and spinal cord, excitatory synapses is the amino acid glutamate. And there are a number of different glutamate receptors that you will find on the postsynaptic cells at a brain or a spinal cord excitatory. synapse. There are two kinds that we normally lump together called AMPA and K-nate that act relatively straightforwardly. In fact, they act very, very similarly to the acetylcholine receptors that we find at the neuromuscular junction. They have a binding site for glutamate. They are permeable to sodium and... permeable to potassium. They have a reversal potential of around zero millivolts, but at normal resting potentials. when you open them up, there's a net flow of sodium in, and you get a nice EPSP, right? Remember, when we have a P, that's potential, which means we're talking about membrane potential. So the membrane potential goes up as you have a net flow of sodium that comes into the cell. So that's relatively straightforward. And much of what goes on inside your brain is just the activity of these sort of regular... receptors, AMPA. I normally refer to them just sort of AMPA receptors, but the K-8 receptors, which are similar, usually get lumped in with them. Now there is a third class of glutamate receptor that you can just see from the description here. The cartoon is way more complicated. These are called NMDA receptors, and they have a binding site for glutamate. But there's all sorts of other crazy things that go on with them. They have to have glycine and amino acid in the synapse as a cofactor to also work. As we will talk about, there's a place where magnesium binds here in the pore. This receptor is blocked by the drug fensiclidine. The other interesting thing that you will notice about this is that in addition to being permeable to sodium and permeable to potassium, it is also permeable to calcium. And remember what we said about calcium, that the presence of calcium inside a cell is normally very, very regulated and very, very low. If calcium comes in, often very interesting things start to happen. And so activating the NMDA receptor allows calcium to come in under certain circumstances, which then has interesting and consequential results. um, for what goes on in your brain. And so, um, we're not going to spend a ton of time talking about those results, uh, today or this week, uh, but later on in the class, we'll see how that plays an important role in how we form memories. Okay. Let's take a look at an IV curve for, uh, a, uh, glutamatergic, uh, synapse. Uh, I'm using the phrase here where we sort of describe a synapse with an adjective. We take part of the neurotransmitter name and we then add the suffix ergic to it. So cholinergic means acetylcholine, glutamatergic means glutamate, gabaergic means gaba. So this is a glutamatergic synapse, meaning the neurotransmitter released is glutamate, but it's got a mix of the different kinds of receptors. And what we see is something that's actually very interesting. First of all, at low membrane potentials you have a net inward current. Reversal potential tends to be around zero. Now what happens is that when you normally stimulate these synapses at very very low membrane potentials, you only get this very very sharp inward current. Again, it's going to depolarize the cell, but you only get a very quick, just a few tens of milliseconds long inward current. And that's all you see. But as you raise the membrane potential up more, you end up getting this sort of longer current that takes longer to come and dies out longer. And if you go to a positive membrane potential, you're going to get an outward current, right? Because now the channel's open and the inside is so positive that more potassium is going to come out. You get this late current also that goes outward. Well, scientists discovered that if you put on a chemical compound called APV, which we know blocks NMDA receptors, then you'd lose this late current. You no longer see the late current. The late current is a consequence of ions coming through the NMDA channel. And so one of the things about the NMDA channel is that its dynamics aren't as fast as the AMPA channel, and it affects the amount of current that goes through it. last a lot longer. The other interesting thing that we see about this late current is that at very, very low membrane potentials, you don't see any late current. In fact, if you look at the current that goes through the NMDA channel, and it's usually abbreviated with an R at the end because it's also a receptor, you see that the amount of current is voltage dependent, right? You have this sort of straight line here where reversal potential of around zero. But then at very, very low membrane potentials, you hardly get any current at all. This actually looks very similar to the IV curve of the voltage-gated sodium channel. Whoops, whose reversal or equilibrium potential is out here, equilibrium potential of sodium. But it's voltage-gated, meaning that below a certain voltage, you hardly get any current. And it turns out... But the NMDA receptor is voltage gated. In the cartoon I showed above, which I have now drawn all over, you will notice that there is a binding site for the ion magnesium. It's actually here in the pore. It turns out that at low voltages, magnesium When the inside of the cell is very negative, magnesium is pulled inward. It's attracted into the cell in the same way that all the ions are attracted into the cell or attracted to be out of the cell based on its electrochemical gradient. Now, magnesium doesn't actually fit through the pore, so it plugs up the pore, right? It sits in the middle of the pore when it's being attracted into the cell. And so when magnesium is plugging the pore, calcium can't get in. Sodium really can't get in. Potassium can't leave. It basically blocks it in a similar way, right, to which the sort of ball and chain on a voltage-gated sodium channel inactivates it. The magnesium plugs up the pore and stops the current from flowing through there. And so if you remove magnesium from the... extracellular fluid, you no longer see this voltage dependence. Now what that means, it has real physiological consequences, is that the NMDA channels, the NMDA receptors, don't pass current until you start to depolarize that postsynaptic cell. They are only turned on when the input into that postsynaptic cell has kind of gotten it already kind of excited. They're kind of like... held in reserve. They won't really open that much under normal quiet circumstances, but if you really activate that cell and really, really bring its dendrites up to a high membrane potential, now the NMDA receptor will be activated. The magnesium actually, right, once the inside starts to become more positive, that magnesium is repelled out of the pore, and now current can start flowing through this channel. So the inside becoming more positive causes the magnesium to pop out. Now the channel can start passing current. And not only does it pass current brought in with sodium, which also lasts a long period of time, it also brings in calcium. And calcium does two things. One, it carries positive charge, which depolarizes the cell. But calcium also plays a role in starting second messenger systems within the cell. and activating other interesting things that can go on in those things later on. So here's an example of a single channel, a single NMDA receptor channel at different voltages. And we're looking at the current when you add glutamate to that mixture, either in the presence of extracellular magnesium or in the absence of it. In the absence... At very, very low voltages, we get a huge inward current because the driving force for sodium and calcium is so high, we get tons of current. But if there's magnesium, we get nothing. But even in the presence of magnesium, if I start getting up to a higher membrane potential, I start to see now this channel is starting to open. And that's because at minus 30, the magnesium is tending to pop out. And if I get even higher, the channels open even more. and an even higher membrane potentials right now. Now the magnesium is gone and the channel acts the same whether there's magnesium around or not.

Usually this sort of refers to both the axon and axon terminal of the cell that's sending the information and then The receiving end of the target neuron, it's often a dendrites or the soma, but not always, as we will see. The neuron that's sending the information, we call the presynaptic neuron. And the neuron that's getting the information, we call the postsynaptic neuron. There's nothing special about presynaptic and postsynaptic. This neuron right here that's sending the information, it's got its own soma and dendrites way back wherever they are.

So it's also a postsynaptic neuron. So this is all relative terminology. A cell isn't presynaptic or postsynaptic inherently. But when we're just looking at two cells combining at a synapse, we'll call one the presynaptic and the other the postsynaptic. All right.

Now, in general, there are two types of synapses. One that tends to be more rare is what's called an electrical synapse. At an electrical synapse.

an action potential or a change in voltage in the presynaptic cell actually flows from one cell to the other and causes a similar change in membrane potential, could be an action potential, in the postsynaptic cell. The electricity, as you can see in this diagram, is just transferred from one to the other. The other kind of synapse, the one that is vastly, vastly more common, is a chemical synapse.

And that's where a neuron releases a chemical signal, neurotransmitters that bind to receptors on the postsynaptic cell. So we'll talk about these in more detail here. Connecting two neurons at an electrical synapse are gap junctions, places that the cell membranes are kind of fused together by these transmembrane proteins. These gap junctions basically allow ions to flow through. And of course, since ions carry the current that causes the membrane potential changes in neurons, this allows the electricity essentially to flow between neurons.

And so here's an example of an electrical synapse where if I inject current into the presynaptic neuron here, this is in the crayfish. I'll get an action potential in that axon. I'm bringing it up to threshold. There is another axon that is connected electrically to this one. And if I measure the membrane potential in that, I see that very shortly afterwards, in fact, within a fraction of a millisecond, I get an action potential in that second neuron, in the postsynaptic neuron.

So we see that electrical signaling is extremely fast. The membrane potential change here in action potential is transmitted from one cell to the other in a fraction of a millisecond. So what does this mean?

It means that electrical synapses are very high fidelity, meaning that a change in one is pretty much directly going to cause a direct change in the other. And it's very, very, very rapid, but it's relatively rigid, right? And so you only get the one response.

It's really great under certain circumstances. Two things that make it really, really useful, and we see them often combined, is of course when you need a really fast response. And so what we see here in this crayfish, if you poke the tail of a crayfish, it will do what is called a tail flip response, where it will contract its very strong tail muscles in response to the...

poke as if maybe a predator was trying to eat it. And that tail flip pushes the animal away from danger. And it's got to be really, really fast because it's an escape reflex.

And also, when you need, and again, this is sort of combined with fast, but fast coordination, this muscular activity, this contraction of its big, thick tail muscle has to be both fast and coordinated so that the animal is pushed properly and that you get maximal force. And so again, tending to be found in the animal kingdom where you need things that are really fast and really coordinated. In particular, we find them at places where animals have need for really fast reflexes. Okay, that's all we're going to say about electrical synapses.

They tend to be relatively rare. We have some in mammals, but not a ton. And most of the synapses that we are going to be talking about in this class and the most of the synapses that we have in our nervous system are of the chemical type.

The chemical type where the presynaptic neuron will release a chemical called a neurotransmitter, and it will bind to receptors on the target neuron and cause interesting things to happen. Okay, so what we're going to do now is we are going to give a quick overview of the process of neurocommunication at a chemical synapse. And then we're just going to keep going into more and more detail.

We're going to go into detail of a classic chemical synapse, which is actually found between neurons and the muscle. Then we'll look at some more specific types of synapses within the central nervous system. And then we'll talk about the details of what different kinds of neurotransmitters do.

But we'll start with the basic process of chemical transmission. And it starts here with a synapse at rest. meaning that there are no chemical signaling between the neurons and no electrical activity in the presynaptic or postsynaptic neuron here.

And what we see is that at rest in an axon terminal, we have these balls, these vesicles, these spheres whose envelopes are made up of cell membrane phospholipid type material. And inside them are packaged neurotransmitters. We call those synaptic vesicles.

And they're just hanging out inside the axon terminal, waiting to be released. Now, what is the signal for the release of neurotransmitters? It's the action potential. So the action potential has two jobs. Its first job is to travel whatever distance the axon is, right?

It's to get the signal from the soma out to the target. And that axon can be really long. It can be going from your spinal cord to your fingertip. It can be going from your toe to your brainstem. It can be going from one side of your brain to another, or it could be just a few microns from nearby cells.

But its job is to carry that information from one place to the other. But when it gets to the axon terminal, it has one last job. And that last job is to, of course, do what it does, which is increase the membrane potential in the axon terminal. When that happens, it activates this special class of calcium channels. These calcium channels are voltage gated.

And so at resting potential, these voltage gated calcium channels are closed. But when the action potential comes in and raises the membrane potential, the voltage gated calcium channels open. Now, if you remember your cell biology, calcium levels are kept very, very low inside most cells, and neurons are no exception. Calcium, the presence of calcium, normally means that something interesting inside the cell is going to happen, and we'll see this in many cases in this class. But here at the axon terminal, the presence of calcium causes these vesicles to dock with the cell membrane at the docking zone.

And when they dock with the cell membrane, they fuse. The vesicles and the contents undergo exocytosis, which releases the neurotransmitter into the synaptic cleft, the tiny space between the two neurons. Exaggerated in distance here. So small that you can't even really see the distance without an electron microscope. Okay.

So the voltage-gated calcium channels, which are normally closed, will open as the action potential, driven by the influx of sodium through voltage-gated sodium channels, raises the membrane potential above the threshold for opening voltage-gated calcium channels. Calcium being really, really highly concentrated outside the cell and not very concentrated inside the cell, now comes into the cell down its electrochemical gradient. That calcium causes the docking of the vesicles.

probably learned about it in cell bio. We're not going to go through the details in this class. Okay, the neurotransmitter, once in the synaptic cleft, is going to just diffuse.

And because the distance is so small, it doesn't take very long for it to diffuse across the synaptic cleft where it binds to receptors on the postsynaptic cell. The binding of the neurotransmitters to these receptors is going to cause some change to occur in the postsynaptic cell. And I'm being deliberately vague about that because we'll talk about the different kinds of change that can occur in a minute.

Now, we don't want those neurotransmitters to continually be activating their receptors. We need some method of sort of stopping the signal from coming. There are a number of ways in which the transmitter is removed from the synaptic cleft, and we'll go through the details later. But sometimes it's brought back into the presynaptic terminal. Sometimes there are enzymes that will chop it up.

So there are a number of different ways in which the neurotransmitter is removed. But those are the general steps. The action potential causes calcium to come in.

Calcium causes the vesicles to be released, the neurotransmitters to be released. Neurotransmitters bind to postsynaptic receptors, which will cause a change in the postsynaptic cell. And then those neurotransmitters are in many ways removed, ending the process. Okay, let's take a look at the...

two major things that can happen when a neurotransmitter binds to a postsynaptic receptor. There are two classes of receptor, each one giving rise to a different kind of transmission. The first kind of transmission we're going to talk about is called fast transmission. In this case, the receptors that the neurotransmitters bind to are also themselves ion channels. So this is a dual purpose protein structure.

It is one, a receptor, and two, an ion channel. It is both. And so we have a couple of different names for this, depending on whether we were referring to it as a receptor or an ion channel. we can call it, since we'll talk about it as a receptor, it is ionotropic receptor, meaning it moves ions. So sometimes you will hear these things referred to as ionotropic receptors, but they're also ion channels, right?

And so let's give them their ion channel name using the Framework that we talked about before, these guys are ligand-gated channels. What opens and closes them? The binding of a ligand.

In this case, the ligands are neurotransmitters. And so they have a binding site. They have a pore region. And they will be open or closed, depending on whether the ligand, the neurotransmitter, is bound.

So they have two names. We'll use both of them depending on kind of how we're talking about them. But in fast transmission, neurotransmitters bind to ligand-gated ion channels or ionotropic receptors. Now, what happens when a neurotransmitter binds to one of these?

When that happens, the ion channels open. And what happens when ion channels open? Ions flow across the membrane. What happens when ions flow across the membrane?

The membrane potential changes depending on which ions are actually flowing. And so the result of fast neural transmission is a change in membrane potential that we call a post... synaptic potential.

And thinking back to my description of how the nervous system works in general, right? We talked about a short-lived transient change in membrane potential that decays as it goes. That is what we're talking about here. That is a postsynaptic potential that came about because of the binding of the neurotransmitters. the opening of those ion channels.

the flowing of the ions across the membrane, bringing their charge with them or taking their charge away, which will change the membrane potential. Now there are two major kinds of postsynaptic potential. There are excitatory postsynaptic potentials, which we abbreviate EPSP, excitatory postsynaptic potential.

These are defined as bringing the neuron closer to its threshold, making it more likely that the cell is going to fire an action potential. Right? Vm, normally at rest, is down here, but threshold is up here. If I bring the cell closer with my EPSP, it is now excited.

It's getting closer to being an action potential. And so excitatory postsynaptic potentials tend to be depolarizing. The other kind is called inhibitory postsynaptic potential or IPSP.

Often, but not always, as we'll talk about later, they are a hyperpolarization of the membrane potential. making the cell harder, making it harder for the cell to generate an action potential. So less chance of an action potential.

You notice I didn't say it brought it closer to threshold because in some cases they do, but they make it harder for the cell to generate an action potential. It inhibits the neuron, making it less likely to send its own signals, less likely to be active. Now, as we mentioned, Neurons take all of these postsynaptic potentials, and if they come in kind of at the same time, right at the axon hillock, they get summed together.

And if that summation of all the incoming postsynaptic potentials reaches threshold, you get action potentials. Here's an example of an inhibitory IPSP combining with an EPSP, and it kind of causes the two to cancel each other out. And so neurons...

integrate information. And again, here's just another description, right? We have IPSP inhibits the EPSPs that you'd normally get from all these inputs that would normally cause action potentials.

IPSP makes the cell less likely to fire an action potential. So the neuron sums all those up and generates its output as a result. So that's fast neurotransmission in a nutshell. Neurotransmitters bind to the binding sites of the ionotropic receptors or the ligand-gated channels, if you want to call them that.

That causes them to open ions across the membrane. Imagine that if you open a sodium channel, sodium is going to come into the cell and raise the voltage, right? Imagine that you open a potassium channel.

Potassium is going to want to leave the cell and it's going to cause the voltage to go down. That would probably be an IPSP. All right. What about slow neural transmission?

Slow neural transmission also involves the binding of neurotransmitters to their receptors. But in this case, those receptors are not themselves ion channels. In fact, we call them metabotropic.

receptors. Metabotropic kind of means you're mobilizing chemical pathways. What happens when neurotransmitters bind to a metabotropic receptor is slow transmission.

And typically what happens is that these receptors, not being ion channels, are going to activate some kind of other set of things that are going on in the cell. Second messenger systems, many of them are G protein coupled, meaning that... When the neurotransmitter binds, you activate the G protein complex, which could do all sorts of other interesting things within the cell.

In some cases, the G protein complex can open ion channels directly or even close ion channels directly. In other cases, the G protein complex is set off all sorts of interesting and diverse sets of processes within the cell. that can do all sorts of interesting things to the cell's properties, kind of like fooling with the cell's settings.

So it doesn't directly change the membrane potential sort of immediately, but as we will see. There are all sorts of subtle things that you can do to a cell to change its properties. And we'll go into more detail about both fast and slow transmission when we look at specific examples. So quick overview, just reminding us how the nervous system works.

Let's take a look at a transmission of information between one cell and another. Let's say this cell here is generating action potentials, which are... all or nothing impulses, right? They are the same height, the whole way along the length of the axon. At the axon terminal, they're going to cause the release of neurotransmitters from this cell here onto its target cell, the presynaptic or the postsynaptic cell.

In fast neurotransmission, that release of neurotransmitter and its binding to the ionotropic receptors is going to cause a postsynaptic potential. We call it graded because if you release a lot of neurotransmitter, you'll get a high EPSP, right? Let's say I have three action potentials coming in. I'll actually release a lot of neurotransmitter.

I'll get a big EPSP. If I only have one action potential, I might get a smaller one. And so that EPSP can be different sizes depending on how much neurotransmitter is released. That EPSP is going to travel to the axon hillock. It's actually going to...

K as it travels. It's not constantly refreshed by opening voltage-gated channels like you have in the axon. And then at the axon hillock, all of the different voltages that are coming in from all the different dendrites in the soma are going to be summed up.

And then this neuron will decide whether to generate action potentials or not. And that'll just continue to bounce around your nervous system until ultimately you'll get to the muscles. right?

The output of your nervous system is to control your muscles. And that brings us to our first example, synapse. Sort of the simplest and the most well-studied and a good place to sort of take a look at some of the very specifics of neurotransmission.

It's the place where your motor neurons, most of which live in your spine, whose cell bodies live in your spinal cord. They send their axons out to your skeletal muscles where they cause a contraction. This is called the neuromuscular junction. It is the junction between the axon and the axon terminal of your motor neurons and your muscle fibers, these parallel pink structures.

And so you can see here, here's one axon that actually activates many, many individual muscle fibers. It's called a motor unit. We'll talk about that later in class.

Here's a cool electron micrograph of it where you can see the axon terminal here. And then underneath it is the place where you would call it the postsynaptic cell. Here we call it in the muscle fiber, we call it the end plate. All right. So let's take a look at this system.

At your neuromuscular junction. You have the axon terminal as we described it before. You have vesicles.

In this case, they are filled with the neurotransmitter acetylcholine. Typically, every neuron will release one type of neurotransmitter. There are exceptions, but normally in terms of like fast neural transmission, there is one type of neurotransmitter that it releases at all of its axon terminals, right? So even though it's branching into multiple places, it's releasing the same neurotransmitter at all of them. And this is kind of a universal feature of neurons.

Obviously there are exceptions, but motor neurons that activate your muscles release acetylcholine, the neurotransmitter acetylcholine, often abbreviated ACH. So the vesicles are filled with acetylcholine. There are voltage-gated calcium channels and voltage-gated sodium and potassium channels for making an action potential. When the action potential gets there, it opens the voltage-gated calcium channels and causes calcium to come in, causes the vesicles to dock, which causes the acetylcholine to be released into the synaptic cleft, or in this case, the neuromuscular junction.

Now, on the muscle fiber, you have receptors and these receptors are really, really dense at the neuromuscular junction. In fact, the neuromuscular junction, the end plate is folded, um, with a zigzag sort of motif, uh, which gives more surface area for having more receptors. Um, Your nervous system and muscular system really, really wants this to be a really powerful synapse so that a single release of neurotransmitter from the motor neuron is going to cause a definitive response in the muscle fiber. If you take physiology, you'll find that that response in the muscle fiber is actually an action potential. But you want to depolarize this muscle fiber reliably.

You don't want... You don't want, at least in the vertebrate nervous system, to integrate information at your muscles. Okay, so there are lots of acetylcholine receptors, and they have, of course, binding sites for the neurotransmitter acetylcholine. Acetylcholine is released into the synaptic cleft of the neuromuscular junction. When acetylcholine binds to this receptor, it opens its pore.

right? This receptor is also an ion channel. It's an ionotropic receptor or a ligand-gated ion channel. When that happens, now ions can flow through. Now you will notice that in this diagram that this channel is actually permeable to both sodium and potassium.

It is a cation channel. It allows positively charged ions through mostly monovalent. cations like sodium and potassium.

So what does that mean for your muscle cell or a neuron that has acetylcholine receptors in them? What's going to happen? Is more sodium going to come in or is more potassium going to leave?

How is this going to change the membrane potential if positive ions are going in both directions? Well, we can study this by making an IV curve. We can hold the voltage of a cell at a particular...

membrane potential. We can then release acetylcholine onto the cell and measure the current that we get as a response. And what we see is that, and here remember, negative current is inward, right? Meaning that this is in and this is out, that positive ions are coming into the cell, right? And so inward current is going to depolarize my cell if I wasn't clamping my voltage.

And so what we see is that at normal resting potentials, there is an inward current, which means that more sodium is coming in through this channel than potassium is leaving. What happens if we clamp the voltage more and more positive? membrane potentials or even no membrane potential or even positive membrane potentials that we see that there's a relatively linear IV curve that goes from inward to outward current at around zero millivolts and then above zero millivolts you actually get a net flow of ions, positive ions, out of the cell, right?

Remember upward here is outward current which will tend to hyperpolarized the cell. Why is this? Well, it turns out that where this line crosses zero, right, where there is zero current, we call that the reversal potential, right? It's the membrane potential where you get no net current.

Tends to be, or is, the average of the equilibrium potentials of the ions that this channel is permeable to. But it's weighted by how permeable the channel is to those ions. It's actually very similar to finding the resting membrane potential using the Goldman equation or thinking about the flow of ions at rest.

Right. It turns out that the in a neuron, the equilibrium potential of sodium is around 50, 55. millivolts and equilibrium potential of potassium is around minus 100. And it turns out that the reversal potential of these channels tends to be around zero. It's kind of a coincidence that it happens to be around zero. There's nothing special about the number zero here.

But if we think about it, it's actually fairly straightforward. At zero millivolts, The driving force on potassium is about twice the driving force on sodium, right? You're twice as far away from... potassium's equilibrium potential as you are from sodiums. Minus 100 here, right?

You're really, really, really not negative enough to keep potassium from leaving. You're also not positive enough to stop sodium from coming in, but sodium is only about half the driving force, right? 50 versus 100 millivolts.

Well, it also turns out that the channel itself is about twice as permeable to sodium as it is to potassium. And so you have twice the driving force for potassium, but half the permeability. And so at zero, which is where you have about twice the driving force for potassium, is where you'll end up with no net flow.

And so you can generate an IV curve here. And here where the line crosses zero, that's not an equilibrium potential. The equilibrium potentials are minus 100. plus 50 of an ion. But for this channel, the reversal potential happens to be, in this case, around zero.

Okay. Now, what actually happens at the muscle fiber as a response to the release of acetylcholine is that because the... current is inward because sodium comes into the cell, you end up with a postsynaptic potential that we actually call the end plate potential, just because we need to have a different name for it in a muscle. It looks just like an EPSB, right?

The VM goes up closer to threshold. It turns out that in a muscle fiber, here's your end plate, it's actually in the middle of the fiber. Immediately surrounding the end plate are voltage-gated sodium and voltage-gated potassium channels. The muscle fiber is actually just like an axon.

And as soon as you depolarize the area around the end plate, you immediately get an action potential that zips away from the neuromuscular junction in opposite directions being carried. and propagated by the voltage-gated sodium and potassium channels that line the cell membrane of a muscle fiber. If you're interested in learning what a muscle fiber does and how it works, you can take physiology.

All right, so that is neurotransmission at sort of a real simple synapse. We actually call it neuromuscular junction. It's got relatively straightforward receptors.

There's one type of receptor, what we call the nicotinic acetylcholine receptor, called nicotinic because it binds nicotine. There are other types of acetylcholine receptors that work in different ways that we will talk about later in the class. Let's move to the central nervous system. Let's now talk about the major classes of the nervous system. synapses that we find in the brain and in the spinal cord.

They tend to be a little bit more complicated, but they work on the same principles. And first, we're going to talk about the major excitatory central synapses. So these are going to be the major excitatory synapses that are one neuron excites another neuron, causes an excitatory postsynaptic potential in it, brings its voltage up higher, closer to threshold.

The neurotransmitter that is released at central, meaning brain and spinal cord, excitatory synapses is the amino acid glutamate. And there are a number of different glutamate receptors that you will find on the postsynaptic cells at a brain or a spinal cord excitatory. synapse. There are two kinds that we normally lump together called AMPA and K-nate that act relatively straightforwardly.

In fact, they act very, very similarly to the acetylcholine receptors that we find at the neuromuscular junction. They have a binding site for glutamate. They are permeable to sodium and... permeable to potassium.

They have a reversal potential of around zero millivolts, but at normal resting potentials. when you open them up, there's a net flow of sodium in, and you get a nice EPSP, right? Remember, when we have a P, that's potential, which means we're talking about membrane potential.

So the membrane potential goes up as you have a net flow of sodium that comes into the cell. So that's relatively straightforward. And much of what goes on inside your brain is just the activity of these sort of regular... receptors, AMPA.

I normally refer to them just sort of AMPA receptors, but the K-8 receptors, which are similar, usually get lumped in with them. Now there is a third class of glutamate receptor that you can just see from the description here. The cartoon is way more complicated.

These are called NMDA receptors, and they have a binding site for glutamate. But there's all sorts of other crazy things that go on with them. They have to have glycine and amino acid in the synapse as a cofactor to also work.

As we will talk about, there's a place where magnesium binds here in the pore. This receptor is blocked by the drug fensiclidine. The other interesting thing that you will notice about this is that in addition to being permeable to sodium and permeable to potassium, it is also permeable to calcium.

And remember what we said about calcium, that the presence of calcium inside a cell is normally very, very regulated and very, very low. If calcium comes in, often very interesting things start to happen. And so activating the NMDA receptor allows calcium to come in under certain circumstances, which then has interesting and consequential results. um, for what goes on in your brain.

And so, um, we're not going to spend a ton of time talking about those results, uh, today or this week, uh, but later on in the class, we'll see how that plays an important role in how we form memories. Okay. Let's take a look at an IV curve for, uh, a, uh, glutamatergic, uh, synapse.

Uh, I'm using the phrase here where we sort of describe a synapse with an adjective. We take part of the neurotransmitter name and we then add the suffix ergic to it. So cholinergic means acetylcholine, glutamatergic means glutamate, gabaergic means gaba. So this is a glutamatergic synapse, meaning the neurotransmitter released is glutamate, but it's got a mix of the different kinds of receptors.

And what we see is something that's actually very interesting. First of all, at low membrane potentials you have a net inward current. Reversal potential tends to be around zero.

Now what happens is that when you normally stimulate these synapses at very very low membrane potentials, you only get this very very sharp inward current. Again, it's going to depolarize the cell, but you only get a very quick, just a few tens of milliseconds long inward current. And that's all you see.

But as you raise the membrane potential up more, you end up getting this sort of longer current that takes longer to come and dies out longer. And if you go to a positive membrane potential, you're going to get an outward current, right? Because now the channel's open and the inside is so positive that more potassium is going to come out.

You get this late current also that goes outward. Well, scientists discovered that if you put on a chemical compound called APV, which we know blocks NMDA receptors, then you'd lose this late current. You no longer see the late current. The late current is a consequence of ions coming through the NMDA channel.

And so one of the things about the NMDA channel is that its dynamics aren't as fast as the AMPA channel, and it affects the amount of current that goes through it. last a lot longer. The other interesting thing that we see about this late current is that at very, very low membrane potentials, you don't see any late current. In fact, if you look at the current that goes through the NMDA channel, and it's usually abbreviated with an R at the end because it's also a receptor, you see that the amount of current is voltage dependent, right?

You have this sort of straight line here where reversal potential of around zero. But then at very, very low membrane potentials, you hardly get any current at all. This actually looks very similar to the IV curve of the voltage-gated sodium channel. Whoops, whose reversal or equilibrium potential is out here, equilibrium potential of sodium.

But it's voltage-gated, meaning that below a certain voltage, you hardly get any current. And it turns out... But the NMDA receptor is voltage gated.

In the cartoon I showed above, which I have now drawn all over, you will notice that there is a binding site for the ion magnesium. It's actually here in the pore. It turns out that at low voltages, magnesium When the inside of the cell is very negative, magnesium is pulled inward.

It's attracted into the cell in the same way that all the ions are attracted into the cell or attracted to be out of the cell based on its electrochemical gradient. Now, magnesium doesn't actually fit through the pore, so it plugs up the pore, right? It sits in the middle of the pore when it's being attracted into the cell.

And so when magnesium is plugging the pore, calcium can't get in. Sodium really can't get in. Potassium can't leave. It basically blocks it in a similar way, right, to which the sort of ball and chain on a voltage-gated sodium channel inactivates it.

The magnesium plugs up the pore and stops the current from flowing through there. And so if you remove magnesium from the... extracellular fluid, you no longer see this voltage dependence. Now what that means, it has real physiological consequences, is that the NMDA channels, the NMDA receptors, don't pass current until you start to depolarize that postsynaptic cell.

They are only turned on when the input into that postsynaptic cell has kind of gotten it already kind of excited. They're kind of like... held in reserve. They won't really open that much under normal quiet circumstances, but if you really activate that cell and really, really bring its dendrites up to a high membrane potential, now the NMDA receptor will be activated.

The magnesium actually, right, once the inside starts to become more positive, that magnesium is repelled out of the pore, and now current can start flowing through this channel. So the inside becoming more positive causes the magnesium to pop out. Now the channel can start passing current. And not only does it pass current brought in with sodium, which also lasts a long period of time, it also brings in calcium.

And calcium does two things. One, it carries positive charge, which depolarizes the cell. But calcium also plays a role in starting second messenger systems within the cell.

and activating other interesting things that can go on in those things later on. So here's an example of a single channel, a single NMDA receptor channel at different voltages. And we're looking at the current when you add glutamate to that mixture, either in the presence of extracellular magnesium or in the absence of it.

In the absence... At very, very low voltages, we get a huge inward current because the driving force for sodium and calcium is so high, we get tons of current. But if there's magnesium, we get nothing. But even in the presence of magnesium, if I start getting up to a higher membrane potential, I start to see now this channel is starting to open.

And that's because at minus 30, the magnesium is tending to pop out. And if I get even higher, the channels open even more. and an even higher membrane potentials right now.

Now the magnesium is gone and the channel acts the same whether there's magnesium around or not.

Transcript for:Understanding Neuron Communication and Synapses

Transcript for:
Understanding Neuron Communication and Synapses