Now, let's consider a couple of properties of Long-Term Potentiation that help us to understand some of the principles at play here. Once principal is called Specificity, and the other is Associativity. Well, the principle of Specificity, means that in order for a pathway to be potentiated, it must be active. So, imagine again the scenario where we have two pathways. One pathway is active and it's stimulated, and that synaptic connection Is going to be strengthened with the application of that high-frequency burst in activity. Meanwhile, another pathway, pathway two, that was not active at the time that pathway one was active, its synapse is not going to be strengthened. So, in order for there to be potentiation of a pathway there must be activity. Activity at that synapse between the pre and the post synaptic partner. Meanwhile, other parallel pathways that are not active will not be strengthened. Okay, now we have the principle of a specificity, and this is extremely important. Now, image we've got two pathways converging upon the same postsynaptic neuron. One pathway is already a strong pathway. That pathway may then be stimulated and it can strengthen even more. Now, the second pathway is weak, that is, it has only a very modest effect on the postsynaptic neuron compared to the first pathway. But if the second pathway, the weak one, is activated concurrently with a strong pathway Then the weak pathway can be strengthened. And this is the principle of associativity. One reason why we think this is so exciting is that this principle of long-term potentiation potentially provides a paradigm for understanding associative learning. Where some reinforcing event, if paired with an event of a neutral nature, can now acquire the significance of the reinforcer. And when we think in those terms, we recognize the basic paradigm of this experiment. The pairing of a strong pathway with a weak pathway can lead to the potentiation of both. Now, unfortunately, I need to digress for just a moment. And clear up an unfortunate error in this figure. this figure unfortunately has duplicated the text from these two blocks. That should not have been in the right hand side of this figure, this word not should be scratched off. So, I'm going to do that digitally by just flying in a little patch. So now we don't see that word not anymore. So, in associativity, the pathways that has weak, but concurrent activity can be strengthened along with the already strong pathway that we stimulated. So, to summarize these principles; specificity means that only active synapses are strengthened. And associativity means that co-active synapses may be strengthened. Now, what I've been telling you about long-term potentiation so far has been well studied in the hippocampus, and it's also been well studied now in many different regions of the cerebral cortex and even in subcortical structures. Well, the details may differ somewhat from one type of gray matter to another. the basic principals of long term potentiation seem to be well established and seem to be present in recognizable forms and all kinds of different parts of the central nervous system when they were discovered. Now many of these mechanisms of long-term potentiation are dependent upon two important different types of glutamate receptors. And so now let's turn our attention to the mechanisms that support this long term potentiation. and to do so let's focus on these tow particular glutamate receptors. One called the AMPA receptor, or AMPA, and the other, then NMDA receptor. These two different kinds of receptors, they're both ionotropic receptors for glutamate, which means that The site for binding Glutamate is part of an ion channel. And both of these ionotropic receptors therefore can mediate rapid conductances in that postsynaptic cell. Well let's look at how they both contribute to the induction and the maintenance of long term potentiation. Now, let's consider first a synapse that has not been stimulated with that high frequency train. So, it's synapse is relatively weak, and it's impact on the postsynaptic cell is fairly modest. So, if this synapse is firing at a fairly low rate. We would expect the postsynaptic cell to remain near it's resting membrane potential. There maybe a small small depolarization that maybe recorded but we wouldn't expect very much at all with low frequency stimulation. So what's happening there is that the action potential and the presynaptic neuron Would be sufficient to induce the release of Glutamate from the synaptic vesicles that are present there. The Glutamate would bind to it's receptors on the AMPA and NMDA receptor channels. The binding of Glutamate to AMPA would open up the pore allowing sodium ions to come in. But again with, low levels of activity we wouldn't expect a whole lot of decolorization to happen at this particular synaptic junction. Well, that would be a bit of problem for our MDA receptors for as you will recall in the poor for the MDA receptor channel there's a binding site for magnesium. Ions and that magnesium is going to blocked the conductance of that channel. Even though glutamates bound and the poor is in it's open configuration, the presence of magnesium is going to block the influx of ions. Well that's what happens when the postsynaptic cell. Is near resting membrane potentials. However, should there be a strong depolarization of that postsynaptic cell, which would be expected if there would be a high frequency train of activity at this synapse, then what we would find is a flood of postsynaptic glutamate. Out of that presynaptic terminal, and perhaps out of surrounding synapses from the same input, that might reach this postsynaptic dendrite. And that might lead to much more significant depolarization in this postsynaptic site. Well, as that happens sodium is coming into the AMPA receptors perhaps a wave of depolarization is passively propagating along the dendrite impacting the spine. There may be sufficient depolarization to expel magnesium from the pore of the NMDA receptor channel. Now, as you know magnesium is a divalent cation, so if the inside of the cell becomes positive, then, then magnesium is going to be repelled out of that channel pore. That will allow that channel now to be available for The influx of sodium ions and calcium ions. As well as the efflux of potassium ions. If you remember what we learned, a few tutorials ago about the NMDA receptor channel. You'll know that it's cation selective. But not particularly selective for with cations that flow. So all three of those cat irons are going to be involved the one that I would highlight however is calcium. So, calcium, very important molecule for reasons that will be clear in just a moment enters through the MDA receptor channel. And with a significant depolarization then we would expect there to be a rapid elevation of postsynaptic calcium levels to a significant degree in this stimulated synaptic junction. That's important, because the rapid elevation of postsynaptic calcium leads to the induction of long term potentiation. Well, let's look at what we know about how that might occur. So, again we're looking at a synapse that has been subject to a strong depolarization perhaps via that high-frequency stimulation that may have been applied in an experiment, or some other means of depolarizing this postsynaptic spine. And under those conditions, what we'll see is a rise in intracellular calcium. And that rise will be sudden, it will be significant, and that intracellular calcium then becomes the key trigger Of second messenger systems that result in the induction and the maintenance of long-term potentiation. So intracellular calcium can interact with second messenger systems such as the protein kinase C system or the calcium calmodulin kinase II system. Both of which will phosphorylate target proteins and among the targets are the mechanism that are involved with the trafficking of AMPA receptors from pools that are associated with vesicles within the postsynaptic spine to the terminal membrane. So as a consequence of this rapid increase in postsynaptic calcium, now AMPA receptors can be inserted in the postsynaptic membrane. And the more AMPA receptors we have in the postsynaptic membrane, the stronger is the response of that postsynaptic neuron to synaptic glutamate. This is a molecular picture of what long-term potentiation actually means at a postsynaptic spine. Well, one consequence of long-term potentiation, especially in the developing brain, is the awakening of silent synapses. Well, what is a silent synapse? A silent synapse is a synapse that is morphologically present and it might be capable of function except that it would lack AMPA recepters. And so here's evidence for one such silent synapse. Imagine stimulating an input to. A postsynaptic cell, while that cell is near its resting membrane potential. And there may not be any measurable post-synaptic potential recorded. So one might imagine that, well, maybe the site of stimulation doesn't connect to that cell. However, if the cell is depolarized with a voltage clamp, one might then record a significant excitatory postsynaptic current. And that is evidence that indeed there is a synaptic connection there. The required depolarization of that postsynaptic neuron implicates a synapse that is populated by MDA receptors and no AMPA receptors. So, what we might find and indeed frequently we do find, especially in the developing brain, are the silent synapses where we have NMDA receptors present only with insufficient numbers of AMPA receptors to make this functional. with low frequency stimulation. However, with the presence of stimuli that can induce long term pretentiation, and these kinds of stimulation events can accrue during the course of development. We see the insertion of AMPA receptors to accompany the NMDA receptors. And so now, a silent synapse has been awakened into a functional synapse, which involves both the presence of NMDA receptors, and now a compliment of AMPA receptors sufficient to mediate the effect of synaptic glutamate. even without significant depolarization of the postsynaptic process. Here's another picture of what this might look like. Before long term potentiation, stimulation of an import might lead to very little postsynaptic current. But after long-term potentiation, the same stimulus might lead to a significant inward current recorded at that synaptic junction. And this suggests that there has been the insertion of new AMPA receptors, possibly even the generation of a new synaptic connection between the presynaptic and postsynaptic dendrite. One can record from circuits in which there's a significant increase in the response of the postsynaptic neuron to glutamate, again indicative of plasticity. Either the awakening of silent synapses, or in some cases the construction of new dendritic spines in response the growth of new synaptic connections. Well, for that to happen, there needs to be a mechanism by which synaptic plasticity over the short run, can influence long-term change, and that requires not just the activation of second-messenger systems that are already present within the postsynaptic spine, but the activation of systems that can trigger a change in gene expression, and that's possible following long-term potentiation. So in the early phase of long-term potentiation, we may see a calcium-dependent increase in the number of AMPA receptors that are inserted, as we've been discussing. But one might also see the growth of new synaptic spines, new synaptic connections. Between presynaptic elements and postsynaptic dendrites. And this requires the activation of transcriptional regulators. And in this cartoon, we see evidence of a protein kinase pathway activating cyclic AMP and protein kinase A and biding to CREB. Which then can regulate the expression of genes that encode for the proteins that are necessary to build new postsynaptic spines to established new synaptic connections. In this way synapses can be added following a stimulus that is sufficient to induce long term potentiation. Now, I would, encourage you to review the roles of ampere receptors and glutamate receptors, and long term potentiation by viewing animation 8.2, you can click on the hyperlink in your. Digital copy of the tutorial notes, or you can browse for yourself to the website that supports the textbook that we have been referring to. And I think you'll enjoy the short animation that will help tie together many of these concepts for you. I would also encourage you to consider the study questions. Which is available at the end of your tutorial, and it's shown here. What I want you to do is I want you to think about why MDA receptors are so important for synaptic plasticity. And I'll give you a couple of possibilities to think about. So, go ahead and answer this question, and register your response accordingly.
