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Synaptic Plasticity John H. Byrne, Ph.D. Professor, Dept of Neurobiology and Anatomy McGovern Medical School The University of Texas Health Science Center at Houston (UTHealth) https://www.youtube.com/watch?v=G-y-bIgQ6MY&t=74s (Links to an external site.) 00:03 Okay. So sometimes a sound, 00:07 even if itís, even if it is the same 00:09 physical intensity, sounds loud and 00:11 other times it sounds kind of soft. 00:14 Sometimes a noxious stimulus might 00:17 feel very painful and other times
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00:20 not so painful. Sometimes 00:22 you remember whatís said in lecture, 00:24 and other times, you donít. 00:27 All these higher level 00:29 phenomenon are due basically 00:32 to the ability of synaptic connections 00:35 to change their strength. So the 00:38 flow of information in feed-forward 00:40 networks. The ability of reciprocal 00:43 excitatory networks to store memories, 00:46 the ability of lateral inhibition to 00:50 produce contrast or edge enhancement
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00:53 can all be regulated by changing the strength 00:56 of the synaptic connections in those networks. 00:59 And thatís the process called synaptic 01:01 plasticity, and thatís what we are going to 01:02 talk about today. 01:04 So thereís two basic types of synaptic plasticity. 01:09 One is called heterosynaptic plasticity; 01:12 the other is called homosynaptic plasticity. 01:15 So, homosynaptic plasticity refers to a
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01:18 change in synaptic strength thatís 01:21 brought about by activity in a single 01:25 neuronal pathway, a single synapse. 01:30 Whereas heterosynaptic plasticity 01:35 is brought about, or is reflected as 01:38 a change in synaptic strength 01:41 between a presynaptic neuron and 01:43 a postsynaptic neuron 01:44 as a result of activity in a 01:47 third, independent pathway. 01:49 So, homosynaptic is SAME. 01:51 The same synapse.
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01:52 Heterosynaptic is a different 01:54 synapse affecting the other synapse. 01:58 So let me just show you, schematically, 02:02 the features of these two types of 02:03 synaptic transmission or plasticity. 02:05 And these two types of synaptic plasticity 02:08 can actually be observed 02:10 at the same synapse. 02:13 Synapse made between a 02:16 1 afferent sensory neuron 02:18 and a spinal motor neuron. 02:21 Now, thereís two flavors
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02:22 of homosynaptic plasticity, 02:25 and thereís two flavors of 02:27 heterosynaptic plasticity. 02:30 For homosynaptic plasticity, 02:31 you can either increase the strength 02:33 of the synapse or you can decrease 02:36 the strength of the synapse. So in one 02:39 case, when itís decreased, 02:41 a phenomenon is called homosynaptic depression. 02:44 And the other case, when the strength of the 02:47 synapse is increased, itís called 02:49 homosynaptic facilitation. So here
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02:52 is the little experimental diagram, 02:55 and here is an example of these two 02:58 flavors of homosynaptic plasticity. 03:01 Here is synaptic depression, and here is synaptic facilitation. 03:06 Letís talk about this one first. 03:08 So, you initiate an action potential in the sensory neuron, 03:11 and you produce an EPSP in the motor neuron 03:14 which is about one mV or so 03:16 in amplitude. This is the EPSP that we talked about 03:20 in the previous lecture. Alright?
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03:21 Now the interesting observation made here is 03:25 that if you initiate an action potential, 03:28 a second action potential, in the sensory 03:29 neuron, soon after the first (In this case, 03:33 the interval is 200 msec, and these 03:35 intervals will become very important 03:37 in our later discussion), 03:39 if you initiate that second action potential, 03:41 the EPSP thatís produced is smaller 03:46 than it was with the first action potential.
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03:48 Itís depressed, right? 03:52 So what are the mechanisms for 03:53 synaptic depression? 03:54 Thereís a number of different 03:56 ways in which this can occur, but 03:59 the predominant mechanism 04:00 Is a phenomenon called depletion. 04:02 So thereís a certain number of (think about it this way) 04:06 thereís a certain number of vesicles in the presynaptic terminal. 04:10 Calcium influx occurs and releases a percentage of those vesicles 04:15 and once some of those vesicles are
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released, 04:17 then there's going to be fewer of them left behind 04:20 to be released the next time. Right. 04:23 Take a very simple example, 04:24 letís say thereís 100 vesicles in the presynaptic terminal. 04:26 An action potential leads to an influx of calcium which 04:32 releases a fixed percentage of those (letís say 10%), 04:33 so the first action potential releases 10% of 100 or 10 vesicles, 04:39 and those 10 vesicles produce a certain
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amplitude EPSP, 04:44 which is say a 1-mV amplitude EPSP. 04:48 So you release 10 vesicles, that leaves 90 left. 04:52 So now if you have a second action potential, 04:55 which allows for a certain amount of calcium influx 04:59 to release 10% of the vesicles again, 05:01 now how many vesicles are going to be released? 05:04 Nine, right? 05:06 So fewer vesicles are going to be released. 05:08 And therefore the postsynaptic receptors that are bound
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05:12 will be less than before 05:14 and the amplitude of the EPSP will be less. 05:18 Pretty straightforward, right? 05:22 We can illustrate that with our M&M synapse, right? 05:25 So, my hand is the calcium 05:29 (No, someone is putting their hand up to protect - 05:31 no, I wonít throw any of this stuff). (laughing) 05:33 My hand is the calcium influx. 05:37 These are the vesicles. 05:38 First action potential comes in here, 05:40 grabs a whole bunch of them, right? 05:42 EPSP 1.
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05:46 Now another action potential, 200 msec later, 05:50 grabs a whole bunch of them. (counts packs of M&M packs) 05:54 1, 2, 3, 4, 5, 6, 7, 8. 05:59 1, 2, 3, 4, 5. Fewer 06:03 Next action potential, 2. 06:08 Next action potential, none 06:12 So here is the depletion of M&Ms, 06:17 and thereís a similar phenomenon, 06:21 depletion of synaptic vesicles, right? 06:24 Thereís a big problem here. What is it? 06:27 No more neurotransmitters.
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06:29 So what do you do? 06:36 You call up the factory, you call up the factory, 06:39 and you order more M&Ms. 06:41 And you fill this back up again okay. 06:45 So, and actually what ës going on in the nervous system 06:50 is we are synthesizing more transmitters and vesicles, 06:52 but what is the nervous system also do? 06:54 Recycles, so it takes, especially for some transmitters 06:59 like glutamate and serotonin, 07:02 thereís an uptake mechanism 07:04 which brings these transmitters
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07:06 and puts them back in the terminal. 07:08 And that's when you have, 07:10 for example, consequences of re-uptake inhibitor, 07:15 inhibitor (sera) SSRI. 07:17 Whatís an SSRI thatís used frequently? (pause) 07:24 Prozac. 07:26 So, if you block this re-uptake process, 07:29 the transmitter stays in this synaptic cleft 07:32 for a longer period of time and its actions are prolonged. 07:36 Thatís a different story. 07:37 You are going to hear more about the ability of synapses
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07:41 to synthesize the transmitter and the re-uptake mechanism 07:44 in the lectures that are going to come shortly, 07:47 by Doctors Waxham and Waymire. (pause) 07:53 Okay, so letís talk about this other process. 07:55 So thatís synaptic depression: 07:57 and we can think about that as being due 07:59 to depletion of the stores of neurotransmitter. 08:03 So, hereís synaptic facilitation. 08:07 The first action produces, action The first action potential produces
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08:11 the 1-mV EPSP that we talked about previously. 08:14 Now hereís the interesting thing, 08:15 The second action potential occurring soon after the first, 08:18 produces a second EPSP 08:21 and now the second EPSP is 2 mV in amplitude. 08:25 You have to extrapolate from the first EPSP, 08:28 but the second EPSP, 08:30 you have the process of temporal summation: 08:32 the two EPSPs are adding. 08:34 But the second EPSP, 08:36 itís intrinsic amplitude is not 1 mV like the first one.
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08:38 Itís twice the amplitude, 08:40 itís 2 mV the total EPSP 08:43 through summation mechanism is 3 mV, 08:45 but the important thing here 08:46 is that the first action potential produces a 1 mV EPSP: 08:51 the second action potential produces a 2 mV EPSP. 08:55 So, how can that be? (pause) 08:59 Well, the explanation for this is a process 09:03 called residual calcium. 09:06 And how it works is shown in this diagram, okay
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09:08 that I think you all have right? 09:10 The diagram up above, by the way, 09:12 is a diagram that expresses, 09:15 or is a reflection or, model of 09:18 the depletion mechanism that we talked about. 09:21 So, you have this basic relationship between calcium 09:24 and transmitter release, we talked about this previously. 09:26 The more calcium, the greater is the probability of releasing transmitter. 09:30 So, normally, you have an influx of calcium
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09:33 and that calcium causes a certain amount of transmitter release. 09:36 But because of that transmitter release, 09:41 the pool of vesicles are depleted, 09:43 so if you have a second action potential 09:45 producing the same amount of calcium influx, 09:47 now you will not be working on this relationship, 09:50 but youíll be working on this lower relationship. 09:54 Because, thereís less vesicles, thereís less vesicles 09:56 that can be released with any amount
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of calcium. 10:00 Here is the facilitation process and the residual calcium model. 10:04 So, what you have to consider now is, 10:06 ìWhat are the consequences of the calcium influx 10:11 that occurs with the first action potential or spike?î Right? 10:15 So the first action potential leads to an influx of calcium 10:17 and that calcium causes a release of transmitter: 10:20 thatís the first EPSP. 10:22 Now, hereís the important thing. 10:24 You have to think about what happened to the calcium
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10:26 that came into the terminal as a result of the first action potential. 10:30 Does it go away instantly? 10:33 No, the calcium does increase. 10:37 The calcium concentration increases, 10:39 but that calcium is going to decrease 10:44 and itís going to decrease for several reasons. 10:46 One is that itís going to be pumped out of the membrane, 10:50 and so we have the calcium pumps we already learned about. 10:52 And also there are buffers within the presynaptic terminal.
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10:56 So, the calcium levels are going to decrease from your peak value, 11:00 illustrated by this second line here. 11:03 Now, hereís the key thing. 11:05 Uh, they are going to decrease, 11:07 but itís going to take some time to decrease. 11:09 So, what if you initiate a second action potential 11:11 during the time window where the calcium levels 11:16 have decreased but they havenít returned to their initial level? 11:20 So the second action potential is going
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to lead 11:23 to the same influx of calcium that the first one did 11:27 but itís going to be, itís going to add to the calcium 11:31 thatís left behind by the first action potential. 11:34 So, the net increase in calciumÖ 11:37 initial increase in calcium was here, 11:39 but now because of the residual calcium 11:41 that second spike adds to the residual, 11:44 and now you get a much greater release of transmitter 11:47 and therefore bigger EPSP.
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11:49 Now some of you should be confused right now, 11:51 because I told you two things that seem mutually exclusive. (pause) 11:59 I told you that this EPSP was smaller 12:03 because we depleted transmitter. 12:06 Well if the first action potential, 12:09 if the first action potential depletes the transmitter, 12:12 so that there is less available 12:15 to be released by the second action potential, 12:18 how can the second action potential (here)
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12:21 produce a greater EPSP? 12:23 Doesnít make sense, does it? (pause) 12:25 And then, thereís something else that doesnít make sense. (pause) 12:36 If this second EPSP produces a bigger EPSP 12:39 (here) why does this second EPSP 12:42 produce a bigger EPSP? (pause) 12:48 Time, (pause) okay time is one answer to solve our problem. 12:53 Itís all about the numbers game here. 12:55 Time is going to solve this problem
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(in the Synaptic Depression example). 12:58 Why is time going to solve this problem? (pause) 13:06 Because, yes, I think youíre right on. 13:09 Time is going to solve thisÖ 13:10 this paradox because the calciumÖ 13:15 we had that model, right? 13:18 You have the influx of calcium that comes in 13:20 and then is recovered 13:22 and then you have the residual calcium. 13:23 Well, this recovery is going to take some time,
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13:26 but itís not going to take 200 msec. 13:29 So by the time you get over here to 200 msec, 13:33 the residual calcium is no longer there. 13:36 So that this influx of calcium to the second action potential 13:39 is the same as the calcium influx of the first action potential. 13:41 So. itís all about the dynamics of the regulation of calcium. (pause) 13:47 Okay, thatís one paradox. 13:49 How do we solve the other paradox? 13:51 How can the amplitude of this EPSP be greater,
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13:56 even though this first EPSP 13:59 led to the depletion of transmitter. 14:02 A greater percentageÖ The answer is, 14:04 a greater percentage of vesicles 14:07 released because of the calcium. (pause) 14:09 Exactly. 14:13 Everybody see it? (pause) 14:17 Okay letís go Ö Yes? (pause) 14:21 Letís go back to our simple example. 14:22 We had 100 vesicles of transmitter. 14:24 The first action potential released 10%. Right?
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14:28 There was a certain amount of calcium available to release vesicles. 14:32 We had 100, we released 10. 14:35 Now that calcium, we had the residual calcium, 14:38 and now the second action potential comes. 14:41 The influx is the same but it adds to what was already there. 14:43 So now, instead of releasing 10%, 14:46 what if we released 20% 14:49 of the vesicles that were there? 14:53 We went from 100 to 90, 14:56 but now we are releasing 20% of 90.
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15:00 Twenty percent of 90 is 18, 15:03 so instead of releasing the 9, we release 18. 15:06 So despite the fact that there is some depletion, 15:09 the increase in the calcium effect overpowers the depletion effect. (pause) 15:17 Got it? 15:19 So you have to think about it, but itís Ö itís really a neat story. 15:21 It involves the dynamics and the relative changes 15:25 in the amount of depletion you get with each action potential. (pause)
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15:33 Okay, thereís another phenomenon that is also interest. 15:36 Itís called post-tetanic potentiation. 15:38 And this is sort of an extreme example. 15:42 This is an extreme example, if you will, of the facilitation. 15:46 I should mention, by the way, that this facilitation 15:48 is also called paired-pulse or twin-pulse facilitation. 15:54 Right? For obvious reasons. 15:56 You have two action potentials,
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15:58 two pulses and you have facilitation. 16:00 Paired-pulse or twin-pulse facilitation, 16:02 So, if you see those, those terms, 16:05 youíll know what they mean. 16:06 So hereís an extreme case. 16:08 In this experiment, again, 16:11 the presynaptic neuron is being stimulated. 16:13 We are recording EPSPs from the postsynaptic neuron. 16:16 Again, this is our spinal motor neuron. 16:18 Here is an example of one of those EPSP, 16:20 as we have seen them before.
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16:22 Now you see these EPSPs, 16:24 they look just a little spikes 16:26 but note the time scale here. 16:28 So, this EPSP in this action potential 16:30 really looks just like this one, 16:33 if you were to load them up at same time. 16:35 So the presynaptic neuron is stimulated, repeatedly, 16:38 at a rate of, looks like here, 16:40 about maybe once every five seconds 16:42 and note that the EPSPs are stable. 16:45 Oh, and that means 16:46 I need to return to a second point about
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this 16:49 If the interval between the first 16:51 and the second EPSP is sufficiently long, 16:53 instead of 200 msec, one second, 16:57 then the second EPSP 16:59 is the same amplitude as the first. 17:01 And why is that? 17:04 Because the vesicles that have been depleted 17:07 have now been restored. 17:10 So the pool sizes have been restored, 17:14 just as we restored our M&Ms synapse. (pause) 17:19 So the EPSPs are stable, with repetition. 17:22 So, hereís an interesting case.
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17:24 Depending uponÖ 17:26 a general statement you can make, 17:27 depending upon the frequency of the 17:29 stimulation of the presynaptic neuron, 17:31 the strength of the synapse 17:33 can remain the same, 17:35 it can get weaker, 17:36 or it can get stronger, 17:38 just by changing the frequency of activity. 17:40 That adds an extra dimension to everything 17:42 we know and think about these neural circuits, 17:45 because their operation is dependent upon
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17:47 the level of activity within the circuits. 17:51 So, here now, instead of just firing two 17:53 action potentials in quick succession, 17:56 you fire a whole burst of these, called the tetanus, 17:59 and you see that, you see the facilitation 18:01 during the tetanus. 18:03 And, whatís interesting here is that 18:05 the change in strength is maintained 18:07 for a sufficient period of time. 18:09 So, thereís like a little memory in this system. 18:12 The strength, the synapse remembers
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18:16 that it had received this high frequency stimulation. 18:19 And this, again, 18:21 is due to the dynamics of the calcium 18:24 buffering within the terminal. 18:26 Okay, now, letís talk about 18:28 the second kind of synaptic plasticity; 18:31 thatís the heterosynaptic plasticity. 18:33 The influence of one synapse on another synapse. 18:36 And to appreciate that you need to just review 18:38 a little about your synaptic morphology. 18:43 Thereís different types of synapses
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that youíve heard about 18:45 already and youíll learn more about. 18:47 Hereís postsynaptic neuron. And this postsynaptic neuron 18:50 receives different types of synapses. 18:53 Some synapses are on the cell body, or soma, 18:55 and these are called Axosomatic synapses. 18:58 Other synapses are on the dendrites. 19:00 These are probably the most 19:02 prominent type of synaptic connections, 19:04 so called Axodendritic synapse. 19:07 And then thereís this other kind of synapse
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19:09 which is very interesting. 19:10 Itís called an Axoaxonic synapse. 19:13 The synapse is not connecting toÖ 19:17 making a conventional connection 19:18 to a postsynaptic neuron. 19:20 The synapse, synaptic connection, 19:21 is made on the synapse of another neuron itself. 19:24 So, because this synapse is 19:26 synapsing with a synapse, 19:29 I think you can see right away 19:30 there is a lot of potential for this synapse 19:33 to regulate the synapse.
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19:35 And just as thereís two flavors of homosynaptic plasticity, 19:39 depression and facilitation, 19:41 thereís two flavors of heterosynaptic plasticity. 19:44 Thereís heterosynaptic inhibition 19:47 and heterosynaptic facilitation. 19:49 So, here is a sort of model diagram of what we just talked about. 19:54 You have a presynaptic neuron, a postsynaptic neuron. 19:56 You have this axoaxonic synapse. 19:58 Weíre gonna just call this neuron. 20:01 Weíre gonna give this a name ìMî
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20:02 ìM1î for modulatory, as we see what that means in a second. 20:06 So here is the basic condition before you activate 20:10 this black neuron. 20:13 The action potential in presynaptic neuron 20:16 produces the EPSP in the postsynaptic neuron. 20:18 Also shown here is the trace showing the influx of calcium. 20:22 So the action potential opens the voltage-dependent 20:25 channels. Then thereís going to be an influx of calcium 20:28 itís gonna have a shape something like this.
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20:29 Okay, now, so this is the control case. 20:33 Now, you fire, produce action potential in this modulatory neuron. 20:38 And then after you do that, you retest the connection, 20:41 and you find out now that the same action potential 20:45 which previously produced this EPSP, 20:48 now produces a much smaller EPSP. 20:52 And you also see Ö so, what this means 20:54 is the strength, the strength of this connection 20:57 between the presynaptic neuron and the postsynaptic neuron
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20:59 is regulated by this other pathway. 21:02 Hence, itís called Presynaptic Inhibition. 21:05 And you see the mechanisms for 21:07 presynaptic inhibition right here on the slide. 21:09 You see that the action potential is about the same, 21:11 as far as you can tell by eye, 21:13 but the influx of calcium associated with that action potential is less. 21:16 Less calcium influx means, less transmitter release. 21:21 So, what is happening here, 21:23 and the details vary from one synapse
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to another, 21:27 is that the modulatory transmitter generally activates 21:29 some type of G-protein coupled receptor 21:33 and that leads to a modulation of membrane channels 21:36 and other processes in the presynaptic terminal, 21:39 and in some cases, the major effect 21:42 is just the modulation of the calcium channel. 21:43 So, what that means is that the same 21:45 action potential which over here produced 21:47 an opening of ìxî amount of calcium
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channels 21:50 now leads to the fact that 21:53 the action potential leads to fewer, 21:56 a fewer, opening of calcium channels, 21:57 therefore less calcium release, 22:00 and less transmitter release. Okay? 22:03 So here is the opposite effect: Presynaptic Facilitation. 22:06 You have a presynaptic neuron, a postsynaptic neuron, 22:09 another modulatory neuron 22:11 (Maybe we shouldnít call this M1; we should call it M2). 22:14 But hereís the basic protocol.
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22:15 You have an action potential in the presynaptic cell. 22:17 You get this EPSP, just as we saw previously. 22:20 Now you activate the modulatory interneuronal pathway, 22:25 that has the axonal axonic synapse, 22:27 and after that, you retest the connection. 22:31 You reintegration the system, and now the same 22:34 presynaptic action potential produces an EPSP 22:37 which is larger than it was previously.
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22:39 Larger was facilitated, and it was facilitated 22:42 as a result of this presynaptic modulatory mechanism. 22:46 So, this neuron releases a modulatory transmitter, 22:51 again engages G-protein coupled receptors, 22:55 again engages second messenger systems. 22:57 Now the consequence of those second messenger systems 23:00 is not to reduce the number of calcium channels that are activated, 23:04 but increase the number of calcium channels
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that can be activated, 23:07 so that now, the action potential leads to a greater influx of calcium, 23:12 and more calcium leads to more transmitters released. 23:16 Okay, letís talk about one further example of synaptic 23:20 plasticity, which is one that is observed 23:22 many synapses in the Central Nervous System, 23:25 and in particular the hippocampus, 23:28 a structure that is critical for memory mechanisms. 23:33 So here is a very schematic diagram
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23:36 of a hippocampal pyramidal cell. 23:39 Notice the triangular structure. 23:42 Itís been impaled with a microelectrode. 23:45 And you see a very crude diagram of a dendrite, 23:48 and on the dendrite are these spines 23:50 that youíve already learned about with Dr. Waymire. 23:53 And there are afferent fibers that 23:56 make contact with these spines. 23:59 One can electrically stimulate the afferent fibers, 24:01 as shown crudely with this little battery and the switch.
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24:03 And you can activate just not one, 24:06 but generally you activate a bunch of these. 24:09 And each one of these will release their transmitter content 24:11 and that will summate through 24:14 temporal summation to produce an EPSP 24:16 in the postsynaptic cell. 24:18 So thatís the basic experiment. 24:20 And hereís some more details 24:22 of the procedure that one uses, 24:25 and also the result. 24:27 So, these little bars here represent the times that
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24:30 you deliver the shock to the presynaptic fiber afferents. 24:35 And shown here on the graph, is the amplitude of the EPSPs. 24:39 Now, weíre not showing their value in millivolts, 24:41 weíre just normalizing them to 100%. 24:44 So whatever the EPSP was initially, 24:46 whether it was five millivolts or seven or 10, 24:48 we just say, ìThatís 100î right? 24:50 One hundred, itís normalized to 100. 24:52 And theyíre stable with repetitive stimulation.
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24:55 Then, at this point in time, you deliver this tetanus; 24:58 this high frequency burst of action potentials. 25:01 And then you return to the initial stimulus frequency. 25:06 And this is what you see. 25:07 There are two phases to 25:10 an enhancement of the synaptic strength: 25:12 one is this initial enhancement, which is the 25:15 Post Tetanic Potentiation (PTP) effect 25:18 weíve already talked about. 25:20 But the other, which lasts for maybe
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several minutes. 22:22 But the other thing that you notice is 25:25 that after the PTP effect dies away, there is an enduring 25:30 and long-term potentiation of the synapse, 25:34 that in this experiment lasts for two hours. 25:37 This is called, for obvious reasons, Long-Term Potentiation (LTP). 25:41 And this just doesnít last for two hours. 25:43 This can last for days, weeks and even months. 25:47 So the remarkable thing here is that 25:50 as a result of this brief burst of activity
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(1 second, 1 second of activity), 25:55 there is a... essentially a permanent change 25:58 in the strength of the synapse. 26:01 So you wonder how you can remember something. 26:03 You have a scene, 26:06 some event in your life 26:09 and you remember it forever. 26:11 Well that event has activated synapses 26:13 in your brain, in your hippocampus, in your cortex 26:16 to produce this LTP phenomenon. 26:19 So your synapse, your synapses 26:21 are permanently altered.
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26:25 How does this work? 26:27 So here is a diagram which seems complicated. 26:30 Weíll go through it slowly, 26:33 but it involves two different types of receptors for glutamate. 26:39 Now one important phenomenon 26:45 that you need to know about, 26:47 and you'll learn a lot about throughout the course, 26:51 is that just as there are different types of neurotransmitters, 26:55 there are different types of neurotransmitter receptors. 26:58 So, for example, thereís acetylcholine.
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27:00 But acetylcholine just doesnít 27:03 bind to one type of receptor, 27:05 thereís at least two different types of receptors: 27:07 the so called nicotinic acetylcholine receptors 27:09 and muscarinic acetylcholine receptors. 27:12 You see these are receptors that both respond to acetylcholine 27:16 but theyíre different. They have different actions. 27:18 And they respond to different agonists, 27:22 so the nicotinic acetylcholine receptors, 27:24 while it responds to acetylcholine,
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27:26 it also responds to nicotine. 27:28 Right. Nicotine, from cigarettes, the same stuff. 27:33 But thereís other receptors that donít respond to nicotine, 27:37 they respond to acetylcholine. 27:39 They donít respond to nicotine, 27:41 but they respond to muscarine. 27:43 So a receptor can respond to different transmitters, 27:46 but thereís special agonists out there for reasons that 27:48 people donít completely understand that
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27:50 will selectively activate 27:52 these different receptors. 27:54 Now for glutamate, 27:56 youíre also going to learn about dopamine receptors, 27:59 Thereís D1 and D2 dopamine receptors. 28:02 ThereísÖ What kind of GABA receptors are there? (pause) 28:07 GABA-1 and GABA-2? 28:11 No. 28:13 Youíre not going to use one or two. 28:15 What would you use as scientists to ...? 28:17 Alpha/beta, you could do that, 29:20 but maybe you could do something even simpler.
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28:22 A and B, so thereís GABA-A receptors, 28:25 and thereís GABA-B receptors. 28:27 And there's different serotonin receptors 28:30 So thereís 5HT. (pause) 28:34 5HTA? 28:36 5HT-Alpha. 28:38 Thereís 5HT-1; thereís 5HT-2, 5HT-3, 5HT-4 and 5HT-5. 28:44 I think thereís actually a 7, too. 28:46 So there's seven different receptors that respond to serotonin. 28:49 So this starts to build up the complexity. 28:51 Not only do you have all of these, all of these different transmitters,
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28:53 but each transmitter can have a number of different receptors, 28:59 Glutamate has two types of receptors 29:01 that are very important. 29:03 One type of receptor that binds to glutamate 29:06 also binds to AMPA, 29:10 and another binds to glutamate and this substance, 29:14 NMDA (N-methyl-D-aspartate). 29:17 So here is a little diagram ... 29:19 And the membrane, the postsynaptic membrane, 29:21 in the hippocampus is interesting because
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it contains 29:25 both AMPA receptors and NMDA receptors. 29:28 So let's just go through one of these 29:31 animations showing what happens 29:33 when glutamate is released from the presynaptic terminal. 29:36 Weíre gonna look at this one. 29:38 So here the glutamate. You got the two little glutamate ions here, 29:40 and two little, not ions, 29:42 two little glutamate molecules here. 29:44 And these glutamate receptors,
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29:46 just like the acetylcholine receptors, 29:48 they need two molecules or transmitter 29:51 in order to produce a conformational change. 29:53 So just like the ACh nicotinic receptor, 29:55 you need two molecules, 29:57 you need two molecules for the glutamate: 30:00 AMPA receptor and the NMDA receptor. 30:03 Okay, so the receptors bind to the channel. 30:07 They produce a conformational change. 30:09 And this channel is just like 30:12 the nicotinic acetylcholine receptor
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30:14 we talked about previously 30:16 as a result of the conformational change 30:18 you have a channel which is 30:21 uniquely permeable and equally permeable 30:24 to sodium and potassium. 30:26 The sodium comes in; 30:27 the potassium goes out, 30:29 and that leads to the EPSP shown here. 30:32 So the story is very much like 30:35 the story we already talked about 30:37 Now take a look. 30:39 Let's go back a second.
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30:41 Take a look at this NMDA receptor. 30:43 So the transmitter has bound to the receptor here 30:46 and is bound to the receptor here. 30:48 This channel is also permeable to sodium and potassium. 30:52 So, but what happens with this channel 30:55 is something really interesting. 30:57 There's some magnesium in the extracellular medium. 31:00 And what happens when this channel starts to open is this 31:03 magnesium that's there, 31:06 comes into the core of the channel,
41:49
31:09 and plugs it up. 31:12 So despite the fact that this channel is open by the transmitter, 31:16 nothing happens because 31:19 it gets plugged up by magnesium. (pause) 31:22 We'd have to agree, that sounds pretty stupid, doesn't it? 31:25 Why would you bother opening 31:28 the channel with glutamate 31:30 when the opening of the channel doesn't do anything? 31:33 So hereís the key, 31:36 and this is why tetanus is important. 31:39 So, remember, to get LTP,
41:56
31:41 this long-term potentiation phenomenon, 31:43 a single action potential doesnít do it, 31:45 because if you repeatedly stimulate 31:47 at a low frequency, 31:49 you donít get any change in synaptic strength. 31:51 Right? 31:52 And you wouldnít really want to do that, 31:54 if you think about it. 31:56 You wouldnít want incidental events in your life, 31:58 to produce these permanent long-term memories. 32:00 You want something important,
42:04
32:02 something that produces a tetanus 32:03 in some of your afferent nerves. 32:05 Something that's important. 32:08 So here's what happens when something important occurs. 32:12 Okay. 32:14 Now, we got, during the tetanus, 32:18 during the tetanus now we have lots of action potentials, right? 32:21 So what's happening is, again, 32:24 the glutamate is released. 32:26 The glutamate is being released, 32:28 and now because of all the action potentials 32:30 weíre getting spatial and temporal
42:11
summation. 32:33 And now the EPSP is getting much larger 32:35 than it was previously. 32:37 Remember, we only had about 1-millivolt EPSP over here? 32:42 Now we're getting this large depolarization. 32:44 Large depolarization. 32:46 Now. hereís the... now hereís the really critical effect. 32:49 Think about what happens when the inside 32:51 of the cell gets positive, 32:53 and what do like charges 32:56 and unlike charges like to do? (pause) 33:00 The inside of the cell gets positive.
42:18
33:03 And what is this magnesium ion 33:06 up here going to think? 33:09 îLet me get the hell out of here 33:11 because I don't like positive. 33:13 I want to get out of that channel 33:15 where itís not positive anymore.î (pause) 33:20 And as a result of the depolarization, 33:22 the magnesium is thrust out of the channel, 33:27 and now something else special happens. 33:29 This channel in addition to being permeable 33:31 to sodium and potassium,
42:24
33:33 is also permeable to calcium. 33:36 And the calcium now can go 33:38 through and enter the cell. 33:40 That calcium that comes in here 33:42 now does some really special things. 33:44 It activates second-messenger systems. 33:46 It activates transcription factors 33:48 that lead to long-term changes in the cell, 33:52 and one of the long-term changes which is produced 33:55 is that now as a result of that calcium influx 33:57 and all of those biochemical changes
42:31
33:59 the downstream effect 34:01 is now the membrane, 34:03 the postsynaptic spine, 34:06 has additional AMPA receptors. 34:09 So additional AMPA receptors are inserted 34:11 into the postsynaptic membrane. 34:14 This was before; we had one AMPA receptor 34:17 and one NMDA receptor. 34:19 And now after, 34:21 we have two AMPA receptors 34:23 and two NMDA receptors. 34:27 Yes? in the back? (listens to the question) 34:33 It doesnít get that positive. 34:36 Think about the driving force.
42:38
34:38 Thatís a good question. 34:39 So, what youíre saying is 34:40 if the inside of the cell gets positive 34:42 and that removes the magnesium, 34:44 so how can the calcium come in? 34:46 Well, you have to think, itís a numbers game. 34:48 Think about the calciumÖ 34:50 the relative concentration of calcium outside 34:52 verses the calcium concentration inside. 34:56 So, now, whatís the consequences. 34:58 So now we go back to the low frequency stimulation.
42:45
35:00 We released the same amount of glutamate 35:02 from the presynaptic terminal, 35:04 but now there's more receptors to bind to, right? 35:07 So, because this, this simple minded case, 35:10 thereís two receptors here, 35:11 only one receptor here, 35:13 you get a EPSP 35:15 which is twice as large as the 35:17 EPSP you got over here. 35:18 Right? So thatís the long term potentiation phenomenon. 35:21 Pretty neat, huh?
42:52
35:22 Youíre going to learn more about this 35:24 in Dr. Waxhamís lecture when you talk more 35:27 about this glutamate transmitter. 35:31 A couple of little summary slides, and we're done. 35:34 This is just to highlight a little bit of both, 35:38 uh, the simplicity and the complexity. 35:40 Here's a postsynaptic neuron. 35:42 Postsynaptic neuron can receive 35:44 contacts from, in some cases, 35:46 ten-thousand different presynaptic neurons, right?
42:59
35:50 Some of these neurons can be, let's see. 35:53 Some of these neurons can be excitatory, 35:55 so there can be ìnî different excitatory neurons. 35:58 There can be ìxî different inhibitory neurons. 36:01 Each one of these synapses can be modulated 36:03 by other interneurons through the process of 36:09 presynaptic inhibition or presynaptic or presynaptic, 36:12 presynaptic inhibition or heterosynaptic inhibition
43:06
36:15 or heterosynaptic facilitation. 36:18 So every one of the synapse can be plastic. 36:21 And thatís the incredible thing. 36:24 So how can you regulate the flow of information 36:26 in a feed-forward network? 36:29 You can change the synaptic strength. 36:32 Right? 36:35 How can you regulate the degree of contrast 36:37 produced by a lateral inhibition circuit? 36:42 Change synaptic strength. 36:44 Change synaptic strength. 36:46 Say it louder for the streamers out there.
43:13
36:48 How can you regulate 36:51 the degree of contrast 36:54 mediated by a lateral inhibition network? 36:57 Change synaptic strength. 37:00 How can you change the gait pattern 37:02 produced by this reciprocal inhibitory network? 37:06 Change the synaptic strength. 37:11 How can you treat a patient with myasthenia gravis? 37:16 Change the synaptic strengthî 37:21 How can you remember neuroscience 37:23 and get an honorís grade? 37:25 Change the synaptic strength. 37:28 Good luck and thank you.
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