We have already traveled from pre-synaptic terminals. What we have discussed was that the action potential generation, the transmitter release, calcium-triggered transmitter release. There's additional machineries that sort of enable vascular fuse with plasma membrane with high specificity and calcium sensor will sense calcium. And then once the transmitter get released, it will activate the postsynaptic receptors. And postsynaptic receptors, upon binding to the specific transmitter, will open. How do they activate the postsynaptic cells or inhibit the postsynaptic cells? And with that, their activation and inhibition, how do they regulate it? For example, how long this activation might be, and how long-lasting they might be? And this is also very important because following that we are going to discuss the molecular aspect of learning and memory. For example, when we are attending this course, something happen in our brain that hopefully we'll remember some of these things. And it's believed that that sort of memory is at least in part occurred at the synapse, at a synaptic level. That is, people believe that when some linear memory happens, there's a modification of the synapse transmission in a long-lasting manner, and that somehow may store the memory. So understanding both of the presynaptic mechanisms of transmitter release and the postsynaptic mechanism will help us to understand. During the linear memory, how the transsynaptor's mission, maybe at a presynaptic terminal or a postsynaptic terminal or both, might achieve this long-lasting modification. And again, just as I said, the communication across the synapse will be action potential generation, and depolarization in the plasma membrane will lead to calcium influx. Transmitter will get released, and release of transmitter will fire to the postsynaptic receptors. Some of the receptors are ligand-gated ion channels that itself will open once the receptor binds to it. Some of the receptors and that will lead to the response of the cell because once they open ion channel, the ion will go through this membrane, will change the membrane potential. And there are other cells, there are other receptors that might, through the second messenger, that might activate this cell in a indirect manner. Second messenger, that will for the empty signal but might be a slower response in the postsynaptic cell. And then the transmitter depends on the type. Some of them will get degraded, so there are some surface-bound enzymes will degrade this transmitter so to limit the timing of these transmitters. And some of these transmitters, again, it depends on the type, they will just simply diffuse so that their concentration will drop dramatically to a level so low that it will not activate the postsynaptic receptors. And some of these transmitters, again, will get transport back to the cell, either direct or indirectly, and to refill the vesicles. And this is the process of the synapse transmission. And the work we are going to discuss, again, studying from the classical work in the postsynaptic mechanism from Bernard Katz, again, a British scientist that we talk about a little bit in the presynaptic field. And this book, even though it's in 1966, Nerve, Muscle, and Synapse still is a classic that summarizeed how the presynaptic and postsynaptic mechanism in terms of ion channels. How the mechanism was identified that lead to our current understanding. So for example, Bernard Katz identified that if we record in the muscles he can record so-called response. That is, if you record in the nerve terminals. And you can see that sometimes the transmitter release will be in a stab manner, the response will be one stab or two stab. For example, there's one peak or two peak. But most of the time if the release probability is low enough, most of the time it's a faded, meaning there's no response. And through his classical work, he demonstrated that the total transmitter release can be signal for a summary or synchronous release of the quantal release. And each individual quanto is corresponding a single vesicle with a pack of maybe 1,000 transmitters. And once they're released it will activate the postsynaptic cells, and that lead to sort of individual step. And sometimes if you have two vesicle simultaneously fuse, then you have two peak or the step size will be two. And more vesicles will be more peaks. And if you have a huge vesicle release, then you can think of maybe 1,000 of those little steps together. And in his recordings, he actually lead to an interesting understanding of how the postsynaptic receptors sense the presynaptic transmitter release originally in the neuromuscular junction. So this is the problem. Again, I'm going to provide you the background, and it's your turn to help me to interpret the results. Are you ready? >> [INAUDIBLE] >> Okay, maybe. So here's what they did. In a neuromuscular junction they can stimulate the nerve. And in this junction, so-called end plate, [FOREIGN], end plate, they can insert electrodes in the muscles to record the response in the muscles. Because of the action potential will propagate into these nerves and you will release acetylcholine and record postsynaptically what you observe will be postsynaptic response. And the postsynaptic response, if it's strong enough, meaning that if the transmitter release are large enough, it will generate an action potential. So what they did is they can record at different locations. So you can put a electrode closer to the end plate or you can move the electrode distance away. And what you observe is here, if you put your electrode very close to the end plate, you observe the postsynaptic response is like this. You have this EPP because end plate potential like here increase. And then, since two has some curve here, then it dramatically increase. That's the action potential. It reaches this threshold and then generate action potential, and then it decays. So this response illustrated a recording near the end plate. In the same muscle, and again muscle is big, even if we were insert several electrodes and if you are careful enough, the muscle are still fine and robust. And you just in the same muscle, you move the electrode 2 millimeters away. So one of them close to the end plate, you put the electrode a little bit far away. And then these dashed lines illustrate the postsynaptic response they got. Again, if you look at this membrane potential, it's an action potential. And then you count slower because of, maybe it's far away from end plate. And then it comes up and goes down. So this is their experiments. Now what is the difference between these two curves? Well, a very obvious difference is the timing. Even with the same stimulation, which illustrate here, the stimulation artifact here. If you are putting electrode closer to the end plate, well, you remember potential will rise faster at the beginning. And if you're putting electrode far away, it will rise up slower. And you can also see the slope, [FOREIGN], the slope of the far away electrode. It's relatively shallow comparing with the slope in the end plate. This is understandable, maybe because once you are releasing a lot of transmitters you are charging the membrane rapidly, and that lead to the threshold. And here the slope is shallower because of this rising phase of the membrane potential relying on the end plate region to charge the adjacent regions. And they are far away, so the charge might be less strong than in the end plate region. But now here's the problem. Here's the difference. If you see the peak of this action potential near the end plate, and the peak here, far away, 2 millimeter away from the end plate, what you clearly see is this peak is larger than this peak. Why this is the case?
