[SOUND] Hello. Welcome to this tutorial on synaptic transmission. Our core concept is, once again, that neurons communicate using both electrical and chemical signals. Now that we've discussed the means for generating electrical signals, we're ready to talk about how chemical signals are used in neuro transmission. We have a couple of learning objectives for you today. first I want you to be able to compare, contrast the structural functional similarities and differences between electrical and chemical synapses. I want you to be able to describe, the sequence of events that's responsible for transmission of neural impulses from one neuron to the next, via a chemical synapse. I want you to consider that process in more depth, and characterize the critical role of calcium in chemical neurotransmission. And lastly, I want you to be able to discuss the mechanisms of action, by which Botox, which is a compound found in nature, and now produced for various clinical and cosmetic procedures, how this compound affects neurotransmission. [SOUND] Let's begin by considering the general structure and function of electrical and chemical synapses. Electrical synapses which are illustrated on the left hand side, function by means of proteins that form channels, called Gap junctions. And these channels, allow for the passage of small ions that carry current directly from the cytoplasm of one neuron to another. Now in contrast, the way chemical synapses work, is via the release of these packages of neurotransmitter into the synaptic cleft. These packages are called synaptic vesicles, and the transmitter itself could be one of a variety of chemical compounds, that has to diffuse across the gap, between neurons in order to have an effect, on the post synaptic neuron. Now in order to compare and contrast, the general function and structure of electrical and chemical synapses, I would invite you to turn to the very end of the tutorial notes that I've given you, and look at the table, where I've try to lay out some general properties that allow us to compare and contrast, electrical and chemical synapses. So, let's begin with some general functional considerations. Electrical synapses allow for, a very rapid communication of electrical signals, from one cell to the next. And this is often very useful. if. it's important to synchronize a local population of cells, that might be in contact with one another via these gap junctions. So here's a slightly more detailed rendering of what a gap junction might look like. So what we see here are, the close apposition of two membranes. so much so that it allows for the pairs of complimentary gap junction proteins, to actually line up in registeration with one another, from across the two cells that are coming together here. So these proteins that form these gap junctions, are called connexons. And they aggregate, to provide an aqueous channel that allows for a current carrying molecule to pass directly from the cytoplasm of one neuron to another neuron. So here's another look at what this might, might look like. So, you can see a variety of connexons that are all, arrayed. Here allowing for ions to pass from one location to another, and with it potentially carrying let's say a positive charge thereby exciting one cell and it's neighbor. Now, as I mentioned, this mediates very rapid synaptic affects so rapid that this is the fastest way that neurons have to communicate one with another. Here in this illustration we see that virtually the same instance that a presynaptic neuron fires an action potential the postsynaptic neuron begins to depolarize towards thresholds, so that it fires an action potential just a fraction of a millisecond after the first action potential in the presynaptic neuron. Now, this can be very useful in a variety of physiological contexts. One is when it's important to synchronize a local population of cells. So look here, we have two neurons that are connected via gap junctions. And when one fires an action potential, not perfectly in sync but very nearly in sync, there are other cells that fire action potentials. So this is important in, certain parts of the central nervous system, such as the hypothalamus. Where a certain quantity of a chemical might be, released into the bloodstream. And in order to get enough of that chemical into the bloodstream, to have the physiological effect, there needs to be synchronization of a whole population of neurons. So that they release their hormone, or they're releasing hormone, virtually at the same moment in time. Now if we back up for just a moment, let's look again at the structure here, of the typical electrical synapse. And I want you to notice that, what's not present. So a few things that are not present: We do not have any vesicles within a presynaptic terminal containing a chemical neurotransmitter. likewise, we do not have a significant synaptic cleft, that is, a gap between the presynaptic neuron and the postsynaptic neuron that must be bridged through some chemical mediator. Rather, we have two membranes that are coming right close together so that the connexon proteins in either membrane can associate with one another forming the gap junction. Now these kinds of electrical synapses can form as two membranes come together, they can form from one dendrite to another from a dendrite to a soma or a cell body, or between two cell bodies, two somatas. Now, one other point about the permeant species that can travel from one cell to another through a gap junction. they're often a current carrying molecule, such as an ion. but there might also be some other small molecule, that's important in second messenger, signalling inside cells, or otherwise important for intercellular communication. small molecules that typically pass through these gap junctions can include calcium ions, they can include ATP, adenosine triphosphate. both of these molecules are important in mediating either tasks that require energy, or the second messenger system, such as a calcium mediated system. That can coordinate the activities between two neurons that are so connected. Now notice also even though the arrows here in this figure are illustrated just going in one direction, that the signals may be bi-directional. That is, ions are free to diffuse down the concentration gradients, or what other permeable molecule we have in mind, such as calcium or ATP. so there's no directionality to the communication here. It can go in both directions. Now, one other point here. The probability of transmission is, is very high. That is, when the gap junctions are open, when the connexons form their channels. Molecules are simply free to diffuse down their concentration gradients, meaning that an electrical signal generated in one cell, will be transmitted to the neighboring cell via the passage of a charge carrying ion with almost 100% certainty. Okay. Now we're ready to consider some general properties, both structural and functional of the typical chemical synapse. And so if we look again at figure 5.1 from your book, we see on the right hand side an illustration of a typical chemical synapse. And here, a few obvious morphological features stand out. First of all, there are synaptic vesicles. that contained chemical substances, that are the neurotransmitters, that will be released as those vessicles fuse with the pre-synaptic terminal. There's a distinct cleft, between the pre and the post synaptic element. And that cleft is an extra cellular space through which the neurotransmitter must diffuse. Now the chemical synapse, this is the principal type of synapse we find in the adult nervous system. I should have made this point earlier, electrical synapses are much more common, throughout the nervous system, as the nervous system is first being constructed in embryogenesis. But with the exception of a few special populations such as in the hypothalamus where we have those hormone secreting cells, and perhaps among some inhibitory cell networks in the cerebral cortex, electrical synapses are not terribly abundant. the principal transfer of information that happens throughout the central nervous system is mediated via chemical synapses. So those are the synapses that we're going to spend the most time over the next couple of tutorials, thinking about their, their function. So, as I mentioned there is a distinct synaptic cleft, so it's not posible then to have, connexin proteins, forming gap junctions or aqeuos pores through which ions can pass directly from one cell to the next. Rather, there's a cleft. So, there's a gap that must be mediated with some chemical message that diffuses across that synaptic cleft. Now in addition to the presence of neurotransmitters of course, we also have receptors for those neurotransmitters, that are found in the post-synaptic membrane. Another distinctive feature of the chemical synapse. chemical synapses typically are from an axon to a dendrite, or more specifically to a small protuberance called a dendritic spine. But chemical synapses can be from an axon terminal directly to a cell body. They can even be from one axon terminal to another. So quite a lot of morphological variations can be seen with chemical synapses as well as with electrical synapses. Now notice that, current does not flow directly from one cell to the next with a chemical synapse. There's this mediator, this neurotransmitter. So once a chemical neurotransmitter has bound to its receptor, something has to happen for there to be the generation of current flow and another action potential in that post synaptic cell. So we're going to take some time to think through exactly how that happens, over the next couple of tutorials. Now with respect to timing, all synapse are fast, but clearly the electrical synapse is designed for the most rapid, most efficient form of transmission. So there's virtually no synaptic delay when it comes to an electrical synapse. But for a chemical synapse, all of these processes that we see outlined here to the right of this figure they all take some time to unfold. So relative to the electrical synapse, the chemical synapse is about maybe four or five times slower. still fast, still maybe about a half millisecond delay at each synaptic junction but still not nearly as fast as the electrical synapse. So chemical synapses are going to be less effective, at synchronizing local populations of neurons than the electrical synapse. A few other points to make. the chemical synapse is unidirectional. That is there's release of transmitter, from the presynaptic terminal and it binds to receptors on the postsynaptic terminal. Now for the aficionados, you'll recognize that there are presynaptic receptors for transmitters. And there might be retrograde signals given off by the postsynaptic cell. But for the most part, information flow is from presynaptic terminal to postsynaptic terminal. Unlike the bidirectional transmission that can clearly happen at the electrical synapse. And lastly, before we leave our table. it's worth noting that the probability of transmission at the chemical synapse, is surprisingly low. for synapses in the brain typically, the probability of there being a postsynaptic spike, given a presynaptic spike is on average somewhere on the order of five to 10%, of course, it varies depending upon the synaptic connection in question. But for the most parts, chemical synapses in the brain, are very weak and they're very unreliable, and there's actually a pretty good reason as to why that might be adaptive. Which we'll talk about when we discuss synaptic plasticity. Okay, at this point, I think we're ready for closer look, at the structure of a typical chemical synapse. So, let's jump back to the first page of your tutorial notes, and Roman numeral three, if you're following along, and let's have a closer look at a chemical synapse. Now, firgure 5.3 is from your textbook. And if you've got the textbook I would highly commend this figure to you. I think it's a very useful figure, for spending some time and studying, and maybe drawing out some of this out for yourself. Because it will really help you understand, some of the fascinating cell biology and the molecular biology that's responsible for chemical synaptic transmission. So, let's follow this figure. And we can, follow along in our notes, which are designed to go right along with what we see in the figure. So, let's consider the sequence of events that unfolds, as an action potential, leads to the release of neurotransmitter in the generation of a post-synaptic signal. This process begins in the steady state and what we find there in the presynaptic terminal are a variety of organelles that are involved in the production of energy. The production of the membrane that's needed to package up neurotransmitters into vesicles, and then the machinery itself. That manages the flow of vesicles and ultimately their fusion with the presynaptic terminal. So we find a variety of important proteins and structures that are present within the synaptic terminal. And I'll show you that in more detail in a few minutes. And we'll just highlight a few of the important members of that cellular machinery as we go along. Now I want you to notice what we have here in this presynaptic terminal, with respect to our synaptic vesicles. So there are some vesicles that seem to be floating freely in that presynaptic terminal. And then there are others that seem to be attached to the presynaptic terminal membrane. So there's a pool of vessicles that are free, and there are a pool of vessicles that are attached. Those that are attached, we call docked. And so these vessels that are docked, are localized near what we call the active zone, which is going to be the site of fusion of those vessicles with the plasma membrane. Those dock vesicles are the ones that are docked and ready to go when an action potential arrives. Okay, so sure enough, an action potential does indeed arrive, at the presynaptic terminal. So this is step number two now, and so a wave of depolarization passively diffuses along this preterminal membrane, until we encounter a voltage gated calcium channel. So near the active zones that are, are numerous voltage gated calcium channels, that are present and as the wave of depolorization hits, those channels open, and now calcium rushes in to the presynaptic terminal. So, step number four here. And this is because there is a steep concentration gradient with more calcium outside, in the extracellular fluid, than inside that presynaptic terminal. The influx of calcium is really key, because as calcium rushes in to that presynaptic terminal. That is the key event that happens in space and time. At the active zone. And in time following the wave of depolarization that hits the active zone. Calcium is what triggers the fusion event that leads to the fusion of the synaptic vesicle with the presynaptic terminal. And the release of neurotransmitter. Okay so, Calcium rushes into the cell and it causes these vesicles to begin to fuse, with the presynaptic terminal membrane. That allows their neurotransmiter to be released into the synaptic cleft via excytosis, a very similar process happens with all other secretory cells in the body. So, the axon terminal, is not particularly unique in that regard, but it certainly is specialized to release neurotransmitter via synaptic fusion events, very rapidly very efficiently. Now, once the neurotransmitter, is released into the synaptic cleft. Then that neurotransmitter, defuses. Where it can interact with a number of post-synaptic receptors. Some of that neurotransmitter, of course, is just free to diffuse away, which it does. But the interaction of the nerve transmitter of the postsynaptic receptor, is what triggers the transfer of the information from presynaptic terminal, to postsynaptic process. If the neurotransmitter binds to a receptor, that happens to open a cation selective channel, then catis can enter that pre-synaptic terminal. That can lead to the depolarization of that post-synaptic site. If this happens over many hundreds, or potentially thousands of terminals on a cell. Then that, very likely, will summate and lead to the depolarization, to threshold of the postsynaptic neuron and an action potential might be generated. without such massive summation, our typical synapse, in the brain is not likely to de polarize the postsynaptic neuron to action potential generation. But nevertheless, this is the general process: Transmitter binds to receptor; receptor can open a cation-selective channel; cations can flow into the cell, leading to their depolariazation. But that's not the only thing that can happen. neurotransmitters can bind to channels that can allow for negatively charged ions, anions, to flow into the cell, such as a chloride ion. That might lead to the sub threshold depolarization of the cell, or, or the hyperpolarization. Depending upon, what the reversal potential is, of the ion channel in question. There are also receptors that, mediate channel closing events. So that can either lead to depolarization, or hyperpolarization depending upon the permeability of that particular channel. So, there's a lot of activities that can occur when a neurotransmitter binds to its postsynaptic receptor. We'll talk about them in more detail over the next couple of tutorials. Alright. So what happens to the neurotransmitter? After it's been released, well I mentioned neurotransmitter's free to diffuse away. for some neurotransmitters at some kinds of synapses, there may actually be an enzyme that degrades that transmitter. In other, systems the glial cell, typically the astrocyte , which is going to be present around synaptic junctions, can actually take up the neurotransmitter. . Or perhaps the metaboloid of that neurotransmitter, and begin a process that will recycle that substance back to the presynaptic terminal. And then finally, the last thing that typically happens, is that the membrane from the synaptic vestical is retrieved ,and recycled. So that the specialized proteins associated with that membrane can be reused, and the membrane itself can be recaptured. Obviously if a synapse, were to simply fuse with all of its vesicles over time, the surface area of that synaptic terminal would continue to expand and, that would not be consistent with the viability of that synaptic structure. So it makes great sense that there's some kind of process that would recycle that synaptic membrane. And indeed there is.