Welcome to this tutorial. This is the first of three devoted to the fascinating topic of synaptic plasticity. in this tutorial, we're going to talk about two particular mechanics, one called long-term potentiation or LTP for short, and the other, long-term depression, LTD. This tutorial will be followed by one that will frame up our understanding of plasticity as is occurs in real brains one spike at a time. And then, lastly, we'll talk about the famous Hebb's postulate and how our understanding of synaptic plasticity is framed up In those terms. Well, this topic relates to several key concepts in the field of neuroscience and they are enumerated below. neuroscience core concepts 2, 4, and 8. We will continue to talk about how neurons communicate through both electrical and chemical signals. And the plasticity that we'll be speaking of in this tutorial relates to plasticity of chemical signaling. And the point of plasticity is that it provides us with a means for life experience to change the nervous system. So we're beginning to talk about some of those most fascinating topics in the field of neuroscience. Those topics that pertain to understanding how the experiences of our lives are transduced into permanent change in the nervous system. All of this holds great promise for the future, fundamental discoveries promote healthy living and the treatment of disease. These topics that we will be exploring in the next few sessions are really giving us a glimpse into the future of medical neuroscience as principles of synaptic plasticity are better understood. So can rational intervention be developed that will harness this amazing plastic potential of the central nervous system for therapeutic advantage. And for those of you that are getting into the healthcare industries these are exciting times. Because, as basic neuroscience progresses and this domain of understanding these principles, so will our capacity to apply these principles for therapeutic good for the patients that you'll come to serve. So, I'm privileged to be a small part of your education that will usher in this new frontier in the world of medical neuroscience, where we will understand how to optimize our capacity to change the nervous system of someone who is dealing with impairment or disease or disability. Or, perhaps someone without those conditions who wants to optimize their performance and whatever domain of life is of concern to them. So, that's what's possible. over the course of your lifetime in your practice, as we come to better understand the brain basis of synaptic change. So I do have some learning objectives for you. I want you to be able to characterize general cellular mechanisms for synaptic change. In particular, I want you to be able to discuss the mechanisms of long-term potentiation. And I want you to focus on two glutamate receptors. The AMPA or AMPA, subtype of glutamate receptor and the NMDA glutamate receptor. And I want you to discuss the role of these receptors in the induction and maintenance in the induction and maintenance of long-term potentiation. Likewise, I want you to characterize long-term depression, and I want you to discuss the molecular basis for long-term depression in two important regions of the central nervous system, the cerebral cortex and the cerebellar cortex. Well, you may not need any motivation at all when it comes to this topic of synaptic plasticity, but again, for those of you that are pursuing careers in healthcare I think it is especially pertinent that you learn these lessons well. one motivating statement, at least for me, has come from one of my colleagues at Emory University who's been a leading thinker and researcher in the translation of basic science discovery in the domain of synaptic plasticity to intervention with people that are dealing with neurological disability. So what Taub and his colleagues have written some years ago in a really excellent review, in Nature Reviews Neuroscience, he wrote that behavior, that is the sensory and motor experiences of our bodies, can have a profound influence on the function and organization of the nervous system... And that this effect can be manipulated to therapeutic advantage in individuals with central nervous system injury. So understanding the rules of plasticity will increase our capacity to help people that are dealing with central nervous system injury and disease. Because, we will better understand how to take the sensory and motor experiences of their own bodies use that capacity to reshape the structure and function of their nervous systems. So let's begin this discussion by making sure we really know what we're talking about when we use this word, plasticity. Plasticity simply means the capacity of the nervous system to change. And, we can think about this concept from a number of different perspectives, and I'd like to suggest a few of them. I'd like to suggest the temperal frame of understanding plasticity. Plasticity can be short-term. Over the course of milliseconds to hundreds of milliseconds to seconds to minutes. It can be long-term. It can last minutes to hours to days to even a lifetime. Just think back for a moment to some of your earliest childhood memories. It's amazing is it not that that is even possible? That some formative event changed the function, maybe even the structure of your nervous system, in such a way that those events can be recalled. now years later, in my case decades later. truly a remarkable achievement for a nervous system to have this capacity to store a lifetime of change. Now, of course, that's not to say that the process of remembering or recalling does not, itself, induce a new round of plasticity, indeed it doe But nevertheless, the basic information that was laid down in the initial event that you and I may be recalling. is still with us. It's still present in the functional architecture of our brains. Amazing. So, our discussion today will begin to get at an explanation as to what may have changed and how w can also consider plasticity in spacial terms. That is, where does plasticity occur? Well, plasticity occurs at synapses. That's what we will talk about today. Plasticity might also occur within the structure and function of the neuron itself. That is, it may simply not be a change at the synapse, but perhaps a change in different compartments within the neuron and the same could be said of glial cells. And in particular, I'm thinking about astrocytes that are important in modulating the activities of neurons within grey matter. Astrocytes themselves are subject to plastic responses induced by changes in their surrounding neural elements. Plasticity can affect the structure and function of entire neurocircuits and entire systems comprised of multiple neurocircuits operating in series and in parallel. Imagine the accrued impact of synaptic plasticity and cellular plasticity throughout an entire neural system. The change can be profound. That change can ultimately be reflected in the organization of functional representations we have in the brain. Consider, for example, the map of the body that we have in our somatic sensory cortex. That map is constantly being updated as we change the use of our body, or perhaps, as the body becomes injured. So, plasticity is a means by which we can constantly update and refresh the learning and the representation that we store, even across an entire cortical area. Well with such change pervasive throughout our organization of neural systems and neural circuits, it's not surprising then that plasticity should be the bases of basically everything we do in our nervous system that is predicated upon learning and change. So, plasticity is the basis of memory, it's the basis of acquiring the motor skill that you may have acquired in life, be it in athletics or perhaps performance arts. Maybe it's in a musical instrument whatever it may be involving the acquisition of motor skill, there's been some plastic change at multiple places in your nervous system that has made that skill possible. The same would apply to cognitive skills. any domain of learning requires that there be some plasticity. Certainly the development of language or the acquisition of new languages throughout life. mathematics for example, the ability to acquire new skills and then apply that knowledge in problem solving. That's another example of plasticity in action, as would be any of the dimensions of the performing arts as I mentioned a moment ago. And finally, again, putting it back into the context of healthcare, adaptation, and recovery from injury or disability requires plasticity within the central nervous system. So, let's just review some of the basic cellular mechanism of plasticity that seem to apply to multiple forms of plasticity. And we'll see how these are played out in different contexts. So, plasticity usually begins when neural activity triggers the activation of postsynaptic second messenger systems. And those second messenger systems usually involve an alteration in the level of intracellular calcium in the postsynaptic neuron. So calcium will be a key index that is used by the postsynaptic neuron to know which way to go with its plastic response. So calcium within the postsynapitc neuron triggers the activity of second messenger systems that often converge on one of two categories of enzymes. one category is the protein kinase family of enzymes these are enzymes, that phosphorylate target proteins. And that's often a mean of turning on that target protein. Another category is phosphatases, and phosphatases are enzymes that dephosphorylate target proteins. So, it's this alteration in protein phosphorylation that mediates the early stages of synaptic plasticity. Where new proteins don't need to be produced, so, so we've not yet really altered the overall protein complement of the post-synaptic cell. We've just altered the function of the proteins that already exist. However, for the long haul, there must be long lasting change in synaptic strength that's brought about by other mechanisms, those mechanisms that involve a change in gene transcription. Well, all of these steps are common to multiple forms of plasticity, and one key differentiator of one form or another is going to be The level of calcium that's present in the post synaptic cell. So, pay attention to where the level of calcium becomes critical for determining what type of plasticity is observed. Okay so now we're ready to talk about one particular mechanism of plasticity called long-term potentiation. But before we can, I need to introduce you to a model system that was foundational for the studies that first brought to light these mechanisms. And that model system is the slice through the hippy campus from a rodent Used as an animal model. So, these experiments can be done, because when an animal is humanely sacrificed and its brain rapidly removed, tissue slices can be obtained from that brain and those slices can actually be kept alive for some period of time. perhaps as long as a day. And during that time, those slices can be probed with microelectrodes, and axons can be stimulated, and the activities of cells can be recorded. And this is what was done from slices obtained from the hippocampus of rodent models, so the hippocampus in the rodent is in the posterior part of the forebrain. And is something of a C-shaped structure with part of in the dorsal aspect of the forebrain, and the rest of it wrapped around the medial margin of the lateral ventrical as it extends in the posterior part of the forebrain. Now in primates, of course, the hippcocampus has rotated further down into an inferior and forward position. So, in primates, the hippocampus would be found in a position of the medial temporal lobe. but of course, rodents don't exactly have a temporal lobe. They have corresponding cortical regions but not a lobular shape per se. Well, be that as it may, it's possible to obtain sections through this hippocampus and keeps those sections alive in a dish, if you will, and manipulate the activity of those cells while recording different populations. This is all done with microelectrodes. So, there's a particular circuit that you should be introduced to in order to make sense of the experiments that I'd like to tell you about and it involves basically a three neuron pathway through the hippocampus. And it begins with inputs that arrive into a part of the hippocampus called the dentate gyrus. And these inputs are coming from the cortex just outside the hippocampus. And something called the entorhinal cortex, part of the parahippocampal gyrus, which you may recall from viewing the surface of the human brain from below. And, these inputs make synaptic connections on a type of cell called the granule cell. The granule cell then sends synaptic inputs to a large pyramidal cell that's found in a region called the CA3 region of the hippocampus. this large pyramidal cell sends axons to several different places. One of them is to a different sector of the hippocampus called the CA1 region. And it's this pathway from CA3 to CA1 that we're going to focus in on and use as our model system. this axon that goes from CA3 to CA1 is called the Schaffer Collateral Axon. And it's possible then to put micro electrodes into this system And stimulate some number of these axons that might be converging on a pyramidal cell in the CA1 region. And the experiments that I'd like tell you about are as follows. A particular microelectrode that is positioned along this pathway is going to be stimulated. So, over time, there may be a brief barrage of electrical pulses applied. This may last just a couple of seconds at a very high frequency and this is called a tetanus. So this kind of tetanic simulation is what will be used to stimulate a pathway and induce long-term potentiation. Meanwhile, a second microelectrode can be positioned to activate a different set of axons that is present and functional, but just not stimulated with a tetanus. Now, to measure the impact of the tetanus in the pathway that's stimulated, as well as the parallel pathway that wasn't tetanized. It's possible just to provide a test shock, maybe about once every 30 seconds. And then, record from this post synapticcell, the amplitude of the excitatory postsynaptic potential, and see what happens to that postsynaptic potential. Does it stay the same? maybe it increases. While this is the base, basic experiment that was performed and the results are shown here. So, Pathway 1 is the pathway that received that tetanic stimulation. So, before the tetanus, a single electrical shock gave rise to a particular excitatory postsynaptic potential of a particular amplitude and a particular bit of rise. But then, after this tetanus, look at what happened. The excitatory postsynaptic potential in the same pathway, in response to a single shock, is about doubled in amplitude. So this is long-term potentiation. Difference in the amplitude of the response of that synapse to the test shock between the prestimulus condition and the poststimulus condition. Something about that brief, tetanic stimulation caused some fundamental change in the strength of this synapse. So, now, it has twice the impact on the postsynaptic cell than it did previously. Now, that was for the pathway that was stimulated with the tetanus. Look at the parallel pathway that was not tetanized. It's present, it's active. In response to a single shock stimulus, it gives rise to a excitatory postsynaptic potential just like the neighboring pathways, only now, before and after the application of the tetanus to Pathway 1, there's no change to Pathway 2. No change, no LTP. Here's another way to look at these data. Plotted here are the responses in these two pathways to the single test shock applied about every 30 seconds or so, for about 15 minutes, before the tetanus to about an hour afterwards. And what we see in Pathway 1 is about a two to threefold increase in the amplitude of the EPSP over time. Now, there is some decay of this potentiation over the course of this experiment lasting about an hour. But nevertheless, after about one hour of time, there is still about a twofold increase in the amplitude of that EPSP, the excitatory postsynaptic potential in the pathway that was tetanized. In the pathway that was not tetanized, there's essentially no change. Now, these initial experiments were done at a time when slices in a dish could be kept alive for about a day or so. but what one really wanted to know was whether this potentiation might be a mechanism of learning and memory over a much longer period of time and that required in vivo experiments. And indeed, this has been done, and we now have a compelling body of data suggesting that long-term potentiation may indeed be the mechanism by which information is stored across a lifetime. Well, this is not a lifetime, but for Rodin, it's still a very long period of time within his lifespan. Notice, that following the application Of o tetanic stimulation, there is a significant increase, in the amplitude of the excitatory postsynaptic potential recorded in vivo, out for about a year's time. So now we're beginning to gain confidence that long term potentiation may be one means of storing information at the synaptic level across a lifetime.
