Welcome to the second of the three tutorials that I have for you about synaptic plasticity. In this tutorial, we're going to talk about spike timing-dependent plasticity. So again our concern is for three very important core concepts in the field of Neuroscience. We continue to talk about the communication among neurons, using electrical and chemical signals. And how life experiences can change the structure and function of the nervous system. And as we learn more about these fundamental properties. We are going to learn how better to promote healthy living and the treatment of disease. So again, this is a very exciting field in modern Neuroscience. And the future couldn't be brighter in terms of anticipating how discovery in the field of Neuroscience is going to improve the human condition. Our learning objectives are again to characterize general cellular mechanisms for synapatic change. And then I want you to be able to discuss the importance of the timing of the postsynaptic response relative to the presynaptic activity. For the mechanism of synaptic plasticity that we observe in the postsynaptic cell. So those are our learning objectives. And to get started, let's review, again, the general cellular mechanisms that lead to synaptic plasticity. Well, we went over this in the previous tutorial and perhaps it bears repetition. synaptic plasticity begins when neural activity triggers the activation of postsynaptic second messenger systems. The trigger in that postsynaptic cell is typically an alteration in the level of intracellular calcium. The level of intracellular calcium is critical, because calcium-dependent second messenger systems are then activated. And those systems can then activate either protein kinases, which phosphorylate target proteins. Or protein phosphatases, which dephosophorylate target proteins. And it's the alteration in protein phosphorylation that either turns on or turns off target proteins. And together, these events mediate the early stages of long-term synaptic plasticity. So these are mechanisms that are operating upon cellular molecular machinery already present within the postsynaptic cell. Long-term synaptic change, however, requires alterations in gene transcription. So this is the general scenario by which plasticity plays out typically in a calcium dependent manner. And the key difference between one valance of plasticity, if you will. Or another, is the level of intracellular calcium that's triggered by the synaptic activity. Well, what I want to tell you about today in this tutorial is, something called spike timing-dependent plasticity. And I want to make clear, I'm not talking about a totally different form of plasticity. Than what we've already discussed in terms of long-term potentiation and long-term depression. Rather, I want to help you understand through this spike timing-dependent framework. How plasticity plays out in ongoing patterns of activity in the brain. Spike timing-dependent plasticity provides for us a framework for understanding plasticity in the brain one postsynaptic spike at a time. And here's what I mean by that. Real synapses seldom, if ever, experience brief trains of high frequency stimulation of the sort. That were used in the hippocampus slice preparations, in order to demonstrate long-term potentiation. So one might reasonably ask. How, then, does plasticity work in real circuits? if they don't experience the kind of stimuli that typically were used at least in the classical studies of long-term potentiation. Well, here's the spike timing-dependent plasticity framework. again, it allows us to understand these principles of plasticity. One spike at a time without necessarily depending upon a special train of stimuli in order to induce a synaptic change. So, consider a synapse where we've got a presynaptic input to a postsynaptic neuron. And in our experiements that I'll be talking about here. It's possible to stimulate the presynaptic axon. And induce a action potential at that presynaptic terminal, at some period of time. Either before or after an action potential is recorded in the postsynaptic neuron. Now if this is a mature, strong synapse. You might anticipate that activity in the presynaptic terminal will lead to the generation of an action potential in the post synaptic cell. And indeed it's possible to find such synapses for which that behavior is observed. And that's what we find in this illustration here in figure 8.18 from your textbook. So, there is an action potential in the presynaptic cell. And about 20 milliseconds later, there is an action potential in the postsynaptic cell. So we call this presynaptic activity before postsynaptic activity. This is what we might expect if our presynaptic cell, let's call that neuron A is firing an action potential. And that leads to the activation of our second cell, we call call that neuron B. So for such a synaptic connection, it's possible to look over time. What is the amplitude of the postsynaptic potential or the postsynaptic current. following some, structured pairing of activity between the pre and the postsynaptic element. And so that's what's being shown here in this recording we have excitatory postsynaptic current amplitude on the y axis. And time on the x axis relative to some structured stimulation between the pre and the postsynaptic element. And what we find is that when we provide that stimulus. Where the presynaptic input happens before the postsynaptic input. Then there is an elevation of the excitatory postsynaptic current. So, the amplitude is increased by about 40%. And so this is evidence of long-term potentiation in this pre-before postsynaptic regime. Now, since we can control the activity with our microelectrodes. It's possible to stimulate the presynaptic terminal. at a time that actually comes following the generation of a postsynaptic action potential. Now, I'll just ask you to remember that our typical neurons that we have in structures like the cerebral cortex recieve inputs from many hundreds even thousands of different synaptic connections. Different exonal inputs converging upon the dendrex at the very same cell. So that cell might fire an action potential in response to activity. And one of these many other hundreds or even thousands of inputs. So, we're studying one particular synaptic connection. And we're varying the timing at which that input is activated relative to the firing of a postsynaptic action potential. So if we stimulate such that the postsynaptic action potential actually happens before the presynaptic action potential. We might find a recording that looks like this. So, the large action potential represents the postsynaptic spike. And then some period of time following it, maybe 30 milliseconds or so later. The presynaptic input is stimulated. And we see some post synaptic potential that's recorded. But that post synaptic potential importantly in this regime follows the triggereing of the action potential. And under that situtation where post synaptic activity happens before pre synatptic activity. Notice that there, now is the development of a weakening. And the amplitude of the excitatory post-synaptic current. This is long-term depression. This is what happens, basically when the postsynaptic neuron is being influenced to fire an action potential by some other input. Other than the one that we're stimulating in this experiment. When experiments such as these can be done over and over again, varying the interval between presynaptic activity and postsynaptic activity. It's possible to generate a function that now accounts for spike time-independent plasticity. And what we see is that in the pre before post regime, that is, when a pre-synaptic input is in a position to fire the postsynaptic cell. There may be a marked degree of potentiation. So this then is long-term potentiation. That can be recorded if the interval between the pre synaptic firing and post synaptic firing is less than about 20 miliseconds. Now 20 milliseconds it's, it's kind of magical interval. if you follow me here, that's an interval that's suggestive of a milo synaptic connection. Where the input in question, the one that we can control with the micro-electrode. Is effective in triggering the action potential in the postsynaptic cell. We might think of this as their as providing some coordination of activity. If you will, between the pre and the postsynaptic element. Where the presynaptic input is reliably leading to the activation of that postsynaptic cell. So pre before post leads to long-term potentiation. On the other hand, again, we're calling that postsynaptic neuron is going to be receiving hundreds of thousands of other inputs. It may fire an action potential in response to some other input than the one that we have control of with our microelectrode. Well, should that happen before the stimulus is applied to the input in question. We might have long-term depression in this post before pre-regime. So this now is long-term depression where the excitatory postsynaptic current is actually diminished. When the firing of the postsynaptic cell precedes the firing of the input in question. So we might imagine that this post before pre is a picture of incoordination between the pre and postsynaptic elements in question. Well, here, in this part of the country, especially as winter is turning into spring. one sport that is popular in my own family, anyway, is baseball. And baseball involves a pitcher throwing a ball at a batter, that has a, wooden or a metal bat. And the batter has to time the swing just right in order to hit that baseball. Well, if the batter begins to swing the bat just at the right moment in time. Then he or she might strike the ball and might hit a homerun. That's a good thing for the batter. We might consider that to be a mediphore for long-term potentiation. If the swing of the bat occurs at just the right time. As the ball is entering the hitting zone. Then the batter begins to pass the bat through the hitting zone and the two make contact and well. That's a good thing for the batter. So we'll call that long-term potentiation. Well, there's a particular kind of pitch in the sport of baseball that's intended to deceive the batter. The batter sees the pitcher release the ball. And the batter anticipates that the ball is going at a faster rate than it actually is. This is called a changeup pitch, meaning a change in the speed of the ball. Well, an effective changeup will result in the batter swinging too early. That is, the bat will pass through the hitting zone before the baseball arrives. I like to think of that, as post before pre. The bat passes through the hitting zone too soon before the opportunity to hit the ball arrives. Well that's not a good thing for the batter. We might call that long-term depression. Well, I was actually invited to think about this metaphor by a student I had a few years ago. Who thought about this spike timing-dependent plasticity function and said, oh, so long-term depression is a near miss. And I thought, exactly, it's a near miss. Like, swinging through a changeup. It's a near miss. The batter swings the bat, but prematurely, before the arrival of the baseball. The postsynaptic activity happens just before the presynaptic activity. That's actually quite bad for that synaptic connection. That leads to the depression of that connection. Whereas if the batter never swung the bat, if it stayed on his or her shoulder, there'd be no strike. Well, I think that's an important lesson. In order for the synaptic connection to be depressed, it actually has to be used. But it has to be used poorly. That is to say, there has to be some incoordination at that synapse. Where the postsynaptic neuron fires in response to some other input. Not the one in question. But it needs to be a near miss. That postsynaptic neuron needs to fire before, but just before the presynaptic neuron. Now, I want you to notice something about the shape of this function. Notice that the shape of the long-term potentiation phase,[SOUND], is roughly about half the width of the shape of the long-term depression function. Well, I think that's kind of interesting. my background is in developmental neurobiology. So I like to think about how plasticity works out in the context of development. And as neural circuits become active, there seems to be a lot of noise and those activity patterns that develop in the brain. We might think of that noise as being somewhat unstructured. And somewhat unshaped by either the brain itself or by it's interactions with the outside world. Well, if the interval for depression is twice as large as the interval for potentiation. Then that suggests that more of that noise is going to fall in the phase of this function that favors depression. Such that the noise is going to tend to lead to the depression of those active synaptic connections. Whereas those synaptic connections that are mediating some structure, where there is preactivty, presynaptic activity leading to postsynaptic activity. That's coordination. So as signal emerges out of the noise of the developing brain, there's the potential to focus in on that signal. Potentiate those synapes that are effectively driving activity in those circuits. And meanwhile depress the other weaker inputs that are out of sync, that are not being coordinated, not being structured. So this may be one mechanism by which the brain imposes a temporal filter on i'ts own activity patterns. As a way of selecting those that are leading to an increase in the coordination of firing across synaptic connections. Well, one way that the brain has of imposing some structure over it's spatial and temporal patterns of activity is through interactions with the environment. And in context of the developing brain, it's intriguing to hypothesize that sensory experience might be one source of structure. That favors the potentiation of functional synaptic connections. Whereas, the noise that otherwise is not being well structured by sensory experience, might lead to depression. And perhaps the weakening, and maybe even the loss and the pruning away of synaptic connections that are, that are not functional. Well, this brings us to the close of this tutorial. The third and final tutorial in this series will put all of this together in a very powerful framework. That has been with us through many decades now and continues to inspire our understanding of synaptic plasticity. So we'll talk about Hebb's Postulate in our next session.
