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0:05
00:00 SYNAPTIC TRANSMISSION AND THE CENTRAL NERVOUS SYSTEM 00:05 Let's now talk about this process of synaptic transmission 00:07 in the Central Nervous System. 00:09 Now that we know how it works at the 00:12 skeletal neuromuscular junction, let's talk about 00:15 synaptic transmission in the Central Nervous System 00:18 and we'll compare and contrast it with mechanisms 00:21 at the neuromuscular junction. 00:24 So, the first slide here just schematically
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illustrates 00:27 the two types of synaptic transmission that I've already 00:31 introduced you to, excitatory synaptic transmission and 00:35 inhibitory synaptic transmission. 00:36 Here's the stretch and knee jerk reflex. 00:37 You activate muscle stretch receptors, action potentials 00:42 then propagate over the dorsal root fibers into the 00:47 spinal cord, where they cause the release of 00:51 transmitter at the terminals of the sensory neurons. 00:55 Synaptic transmitters release, diffuses
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across the cleft, 00:58 bind to receptors on the postsynaptic motor neuron, 01:02 which then produces a depolarization, 01:05 which then leads to an action potential in the motor neuron, 01:08 propagation out the peripheral nerve to invade this synapse. 01:11 This is the synapse we spent all last lecture talking about, 01:14 the synapse at the skeletal neuromuscular junction. 01:17 This one releases the acetylcholine to produce the endplate potential.
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01:21 Now we are going to talk about this synapse and this synapse, okay? 01:25 So, already I gave you a hint of what happens. 01:30 What happens, and it is essentially the same thing, 01:32 in many respects as what happens here, the action potential 01:35 invades the presynaptic terminal, causes the release of transmitter, 01:39 produces an EPSP in the motor neuron, 01:42 an excitatory postsynaptic potential that 01:44 propagates out there and we get the reflex. 01:45 So here is a cartoon,
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01:48 showing in a little more detail, the connections. 01:52 So here is the sensory neuron connection 01:54 to the extensor motor neuron. 01:56 The sensory neuron also connects to this dark cell, 02:00 the interneuron. An interneuron is a cell interposed 02:02 between one neuron and another neuron, and one can 02:06 impale the presynaptic sensory neuron 02:07 with an electrode to produce an action potential. 02:10 One can record from the postsynaptic
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neuron. As a result 02:15 of an action potential in the presynaptic neuron, 02:18 you produce this excitatory postsynaptic potential 02:22 in the motor neuron, the EPSP. 02:25 So the EPSP is the general term. 02:26 We talked about a specific EPSP 02:28 at the neuromuscular junction that was called 02:30 the motor endplate or the endplate potential. 02:31 But in general, itís an EPSP, 02:33 an Excitatory Post Synaptic Potential. 02:39 So, what are the ionic mechanisms of
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the endplate potential, 02:43 of the EPSP in the Central Nervous System? 02:45 We talked about the ionic mechanisms of the endplate potential. 02:48 The simultaneous increase in sodium, potassium permeability. 02:51 Turns out the ionic mechanisms, here, for the production of EPSP, 02:55 are identical as a result of the transmitter substance, 02:58 diffusing across the cleft, it binds to receptors 03:01 on the postsynaptic membrane producing an
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03:03 equal increase in sodium potassium permeability, 03:05 moving the membrane potential in the depolarizing direction, 03:09 producing the EPSP. 03:11 Now, thereís two. So thatís the similarity. 03:15 Thereís two major, major differences 03:18 between synaptic transmission in the Central Nervous System 03:21 and in the neuromuscular junction. 03:27 And you can see one of the differences right here, 03:29 I donít even have to tell you, you
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can see with your eye. 03:33 So take a look at this scale bar. 03:36 Itís a 1 millivolt scale bar. 03:39 Whatís the amplitude of the EPSP recorded in the motor neuron? 03:45 About one millivolt 03:48 Whatís the amplitude of the EPSP recorded 03:49 at the neuromuscular junction? 0.5? 03:58 That was the miniature endplate potential, was 0.5. 04:02 The endplate potential was 50 Ö 50.. 04:08 So, big differences. This is 1 mV.
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04:12 The endplate potential is 50 mV. 04:15 Big difference in the amplitude. 04:17 The other difference is not evident here, 04:20 but itís in the neurotransmitter substance thatís released. 04:24 Whereas, at the neuromuscular junction, 04:26 the neurotransmitter substance released 04:29 at this synapse was acetylcholine. 04:32 The neurotransmitter substance released at THIS synapse 04:35 is not acetylcholine.
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04:38 It is glutamate, an amino acid neurotransmitter. 04:43 So, that leads us to this very general aspect 04:50 of synaptic transmission is that there are more than one 04:52 neurotransmitter substances. 04:54 The mechanisms of release are similar at all synapses. 04:59 The calcium influx, causing the release of vesicles. 05:02 The synapses, they look, they look, 05:04 very similar, you know, in their structure. 05:07 Hereís a synapse from the neuromuscular junction.
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05:10 You know whatís coming? 05:12 Hereís a synapse from the spinal cord. 05:18 You release this one (tosses out packs of plain M&Mís) 05:21 and you get the M&Mís. 05:24 And whatís the difference in this synapse? 05:27 Different flavor, different flavor, different flavored M&Mís.(holds up packs of peanut M&Mís) 05:33 This is what everyoneís been waiting for, the peanut M&Mís, I know. 05:39 So this also illustrates another phenomenon
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05:41 of synaptic transmitter release. 05:43 When you release the transmitter, 05:46 it doesnít all reach receptors, you know. 05:50 See, some of it misses, so you are going to waste some 05:52 when you, when you release the transmitter. 05:55 Okay, you all have this handout (Shows handout: Neurotransmitters 101), 06:00 So this appeared in Newsweek in 2008. 06:05 This is Neurotransmitter 101. 06:07 So this is what the general public knows
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about neurotransmitters, 06:09 so you need to know at least this, right? 06:12 Because everybodyís gonna ask you, you know, 06:15 ìWhat is acetylcholine do? 06:18 What does serotonin do? 06:20 Whatís with dopamine? 06:21 You know, whatís with GABA?î 06:24 And theyíre going to also ask you about their diseases, soÖ 06:30 You all know about Prozac? 06:33 What does Prozac do? 06:37 What disease or disorder? 06:39 Depression? 06:40 How does Prozac work? 06:42 Whatís itís mechanism of action?
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06:47 SSRI, itís an SSRI - serotonin reuptake inhibitor. 06:51 So it affects the serotonin neurotransmission system. 06:56 What about Valium? 06:58 Youíve all heard about Valium. 07:00 You probably know someone who takes Valium. 07:04 What would they take Valium for? 07:09 A sleep disorder? 07:11 Could be. 07:12 Anxiety, in general. 07:15 How does Valium work? 07:21 It inhibits GABA? 07:24 No, that would, inhibiting GABA, 07:27 would be a bad thing to do.
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07:29 GABA is a transmitter that has an inhibitory effect. 07:33 It potentiates GABA effects, so it potentiates inhibition. 07:36 We already talked about neostigmine. 07:41 ACh inhibitors. 07:43 We talked about Alzheimerís Disease effects. 07:47 L-Dopa. 07:50 Parkinsonís Disease. 07:52 And what transmitter system are we affecting there with Parkinsonís Disease? 07:56 What does L-Dopa do? 07:58 It boosts the synthesis of what transmitter? 08:03 Dopamine. 08:06 How does cocaine have its effect?
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08:15 It releases, it releases all the dopamine? 08:19 Well, not exactly. 08:24 Excuse me, what is the answer? 08:26 It inhibits reuptake. 08:28 So, so cocaine is a dopamine reuptake inhibitor. 08:33 So, the point I am trying to make here is that 08:36 thereís lots of different neurotransmitters, 08:39 and when thereís lots of different neurotransmitters, 08:40 thereís lots of different ways things can go wrong. 08:43 And thereís millions of Americans that
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are affected by disorders, 08:48 affected, that are involved neurotransmitter systems, 08:52 so you need to know these neurotransmitters 08:55 and how they are affected by different drugs. 08:56 Okay, one consequence here of this small EPSP is. 09:00 Okay If this EPSP is so small, only 1 mV in amplitude, 09:03 the obvious question is Ö Well, hold it a second! 09:09 How can an action potential in this presynaptic cell 09:12 produce an action potential in the postsynaptic cell
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09:15 and the subsequent contraction of the muscle cell? 09:19 There was no problem when we talked about this 09:22 because the endplate potential released by, 09:25 produced by, a single action potential here, 09:27 produces the endplate potential of 50 mV, 09:30 producing an action potential. 09:33 This EPSP is only 1 mV, 09:35 so it seems like we are doomed for failure. (pause) 09:46 This is why when you do that test to yourself, 09:49 it never seems to work. 09:53 Okay, whatís the answer?
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09:56 Summation; the answer is summation. 09:58 And thereís two kinds of summation. 09:59 Thereís something called temporal summation, 10:00 and there's something called spatial summation. Alright. 10:03 So here is a diagram of a motor neuron, 10:08 and these motor neurons, we already know from the first lecture, 10:11 they donít just receive contacts from one sensory neuron, 10:15 they receive contacts from multiple sensory neurons
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10:17 through a process called (pause, waiting for student response). 10:24 No... we talked about those microcircuits, 10:27 whose microcircuit A, B, C... 10:30 Convergence. 10:32 Convergence, yes. 10:33 So here is an example of temporal summation. 10:38 An action potential in one neuron. 10:41 Right, this is just a simple diagram, 10:44 itís two neurons: sensory neuron 1, sensory neuron 2. 10:47 Letís just talk about sensory neuron 1. 10:49 An action potential in sensory neuron
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1 produces this EPSP. 10:52 Itís small, hereís the calibration bar, only 1 mV. 10:55 But if you fire or initiate two action potentials in quick succession, 10:59 look what happens: 11:01 the second EPSP adds on to the potential produced by the first. 11:05 Right?11:06 It is like if you were to take your flame and touch it 11:10 not just once (the flame of a lighter against your finger) but twice, 11:12 the temperature is going to get; yeh, that hurt. (students laugh)
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11:16 The temperature, the temperature is going to build up, 11:19 it is going to add up, and so it's going be greater 11:21 than that produced by a single stimulus. 11:24 Alright? So thatís temporal summation. 11:26 And, of course, when you have stretched the muscle, 11:29 you just donít activate one action potential in a sensory neuron, 11:35 unless that stretch is very, very weak, 11:37 itís going to activate multiple action
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potentials in the sensory neuron. 11:41 The frequency of which is dependent upon the strength of the stimulus. Right? 11:46 Now hereís spatial summation: sensory neuron 1 and sensory neuron 2. 11:50 Now we are talking about two sensory neurons 11:52 that converge onto the single motor neuron. 11:56 Sensory neuron 1 produces that 1-mV EPSP by itself. 11:59 Sensory neuron 2 produces the 1-mV EPSP by itself. 12:03 The two together, they add up and they
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produce a 2 mV EPSP. 12:07 That's like having two cigarette lighters and doing them at the same time. 12:11 Youíre going to get twice the temperature, 12:13 if the you're doing them at the same time, than just one. 12:18 Okay, now we are going to talk about that other neuron, 12:21 the inhibitory neuron. 12:22 Remember the spinal circuit? 12:23 The sensory neuron activated the neuron, 12:25 the interneuron. 12:27 And the interneuron in turn releases 12:29 neurotransmitter substance.
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12:31 As a consequence of that neurotransmitter substance, 12:33 now we donít have an EPSP in the flexor motor neuron. 12:38 We actually have an increase in the hyperpolarized state 12:42 an inhibitory postsynaptic potential, 12:45 because the membrane potential 12:46 is moving further away from threshold. 12:49 And those IPSPs move the membrane away 12:56 from threshold, and if you have IPSPs 12:58 at the same time as EPSPs, the IPSPs
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13:00 can prevent the excitatory information 13:03 from activating a motor neuron. 13:06 As we mentioned earlier, this process 13:09 by which, process by which a postsynaptic neuron 13:12 adds up the excitatory and the inhibitory input is called what? 13:19 Summation? 13:21 Thereís a more technical term. 13:24 CalculusÖ think about calculus, 13:26 what happens in calculusÖ Integration! 13:28 Thank you. 13:31 What about the ionic mechanism of these IPSPs?
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13:33 EPSPs are due to an increase in simultaneous 13:37 permeability to sodium and potassium. 13:40 What might be the ionic mechanism for an IPSP? 13:46 In principle, how could you do it? (pause for student answers) 13:55 Increase potassium permeability, 13:57 right, so the membrane potential is negative, 13:59 but it's not, it can be more negative. 14:01 Potassium equilibrium potential is -75; right? 14:04 The resting potential is -60. 14:06 So if you could increase the potassium
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permeability, 14:09 you could in principle, 14:11 by a neurotransmitter opening a channel, 14:13 you could in principle produce an IPSP, 14:15 and thatís the way it works in some cases, 14:17 but not in this particular case in the spinal motor neuron. 14:19 In this case in the spinal motor neuron, 14:21 you increase the chloride permeability. 14:24 Equilibrium potential for chloride 14:26 is more negative than the resting potential,
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14:28 so if you increase the chloride permeability, 14:30 you get a hyperpolarization. 14:33 Whatís the neurotransmitter substance 14:36 released by this interneuron? 14:39 GABA? No. 14:45 Dopa, no such transmitter. 14:48 Glycine. So itís an amino acid transmitter. 14:51 So the excitatory transmitter is glutamate, 14:53 thatís an amino acid transmitter. 14:55 Another amino acid transmitter is glycine, 14:57 and glycine is the transmitter that is released at,
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15:01 at this synapse. 15:04 People mention GABA. 15:07 GABA is a very prominent transmitter that has 15:09 inhibitory actions in the Central Nervous System 15:12 but not at this particular inhibitory connection. 15:14 In most cases, inhibitory synapses use GABA. 15:17 Glycine is kind of the exception, 15:19 thatís the ones used in the spinal cord. 15:21 But again GABA is another amino acid transmitter. 15:25 So, you have glutamate, glycine, GABA.
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15:27 A number of different amino acid transmitters. 15:29 Thereís Ö the complication is that thereís 15:31 probably fifty neurotransmit..., 15:33 fifty or more different neurotransmitter substances. 15:35 Youíre going to learn about these next week. 15:37 You are going to start to learn 15:39 more about them this week. 15:40 They are very important. 15:42 They have all kinds of clinical implications. 15:44 The good news is that despite the fact that
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15:46 thereís maybe fifty different transmitters, 15:49 they can be broken down or divided into different categories, 15:53 so if you learn about one category, 15:56 you learn a lot about the individual members of, 15:59 of that family. 16:01 So what are the categories of different neurotransmitters? (pause for student answers) 16:07 Acetylcholine? 16:11 Acetylcholine is in a category by itself. 16:16 Acetylcholine and thatís the only member of that family. 16:19 Then you have monoamines.
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16:21 So, who/what are the family members? (pause for student answers) 16:27 We talked about them. 16:30 SSRI. Serotonin, Another? (pause for student answers) 16:42 What did you say? The monoamines? 16:45 Uh, yes. So whatís the last syllable there? 16:49 Yeah, okay. Whatís another? (inaudible) No. 16:53 Dopamine? Dopamine. Serotonin. Norepinepherine. 16:58 All members of the -amine family. 17:02 Another category? 17:04 Peptide transmitters is a huge family
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of different transmitters. 17:06 You are going to learn about all of these 17:07 different transmitter systems as we go 17:09 throughout the course. 17:11 So, just want to conclude with this other major, 17:16 different type of transmitter action. 17:19 And, it's illustrated in this slide. 17:24 Here you have a postsynaptic neuron 17:26 that receives synaptic connections 17:28 from two different presynaptic neurons: 17:29 neuron 1 and neuron 2.
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17:31 And as a result of an action potential in this neuron, 17:33 you produce this EPSP that has amplitude of about 1 mV, 17:38 and you see its duration is about 10-20 milliseconds duration. 17:41 This is the kinds of EPSPs that we talked about previously, 17:46 at the neuromuscular junction, 17:48 at the synapse between the sensory neuron 17:49 and a motor neuron in the spinal cord, 17:51 meeting at the stretch reflex.
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17:53 Itís called a Fast EPSP. Why? 17:55 Because itís fast and itís in contrast to this 17:59 EPSP produced by neuron 2, 18:01 and it produces an EPSP like the depolarization, 18:06 like the one in part B1, but notice the time scale here. 18:09 This is a 20 millisecond calibration bar. 18:12 So this one is orders of magnitude longer 18:14 in duration than this EPSP, 18:17 and this is obviously 18:19 called the slow EPSP. 18:21 But itís just not fast and slow;
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18:23 they are due to very different mechanisms. 18:26 So, the fast EPSP is also called an 18:28 ionotropic synaptic action, because it is due 18:32 to the opening of an ion channel. 18:33 A direct binding of the transmitter 18:36 to the ion channel, it's called inotropic 18:39 This EPSP is called the metabotropic effect. 18:42 A metabotropic EPSP because 18:45 it is due to a receptor binding, 18:48 a transmitter binding to a receptor
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18:51 which then leads to the engagement 18:53 of some second-messenger system as shown here. 18:56 So as a result of binding to the receptor, 18:58 Dr. Waxham is going to tell you more about 19:00 these specific types of receptors that bind 19:03 to these transmitters you lead to an 19:05 increased synthesis of second messengers, 19:07 like in this case, cyclic AMP (cAMP). 19:09 And now, cAMP is leading to 19:11 the activation of the cAMP-dependent protein,
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19:12 kinase, and now that phosphorylase a membrane channel, 19:17 and as a result of the phosphorylation in this case, 19:19 there is a phosphorylation of a channel 19:21 which is normally permeable to potassium 19:24 as a result of the phosphorylation, this channel closes. 19:27 And when you decrease the potassium permeability, 19:30 that is going to produce a depolarization. 19:33 So, as a contrast to a transmitter directly binding 19:39 to the receptor channel complex,
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19:41 this is much more complicated. 19:43 It involves intermediary steps. 19:45 And now I think you can clearly see 19:47 why this is slow, compared to this being fast. 19:50 Why is this slow? (pause for answers) 19:54 First of all, I should say, why is this fast? 19:56 It is fast because you release the transmitter, 19:58 and the decline is due to the removal of the transmitter. 20:01 The transmitter doesnít bind instantaneously.
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20:03 Itís removed by diffusion or by acetylcholinesterase, 20:06 in the case of acetylcholine transmitter, 20:09 transmission or re-uptake 20:11 in the case of amino acid transmitters. 20:12 The transmitter is rapidly taken away 20:16 and so the conductance change decreases 20:19 as the transmitter no longer binds to the receptor. 20:21 Here, what you have is this second messenger system 20:24 so the duration of the EPSP 20:27 is dependent upon the duration of phosphorylation.
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20:30 What regulates the duration of the phosphorylation? (pause for student answers) 20:36 The duration of the cAMP synthesis, which is slow, 20:39 the phosphorylation by PKA, which is slow. 20:42 And the persistence is dependent on how long 20:45 the channel remains phosphorylated. 20:47 And that is regulated by (pause for student answers) 20:51 some special chemicals called (pause for student answers) 20:57 phosphatases. 20:59 So phosphatases remove the phosphate group, so,
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21:02 the bottom line is that the duration of the EPSP 21:05 is dependent upon the duration 21:07 of the actions of the second messengers systems 21:09 and the phosphatases. 21:14 Okay, so in the next lecture, 21:18 what we are going to do is talk about synaptic plasticity. 21:21 So it is easy to think of synaptic transmission 21:24 and neural circuits as being hardwired, 21:27 just like the solder joints in an electrical circuit. 21:30 A certain synaptic connection always
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21:33 has the same strength: 1 mV, 50 mV, 5 mV, whatever; 21:36 itís the same strength. 21:38 It turns out that the strength of synapses changes dramatically, 21:42 changes as a result of activity, 21:45 and also changes as a result 21:47 of important behavioral actions, 21:50 like learning and memory. 21:52 So, in the next lecture on Wednesday, 21:54 we are going to talk about this phenomenon of synaptic plasticity,
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21:56 which endows synapses with the property, 21:59 property of changing their strength. 22:03 Okay, so weíll have an early lunch, 22:05 and we will see you on Wednesday.
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