| 00:02 | All right, this is our lecture of neuroscience and we're scheduled to talk |
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| 00:09 | central nervous system. One, in , we're going to be finishing up |
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| 00:14 | neural transmission, talking about some of things that we already started and didn't |
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| 00:19 | from last collect materials. So without ado this is where we ended, |
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| 00:24 | ended talking about glutamatergic synaptic transmission. we understood the callergy synaptic transmission very |
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| 00:31 | . Then we started talking about glug transmission. So once glutamate is |
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| 00:35 | it's a natural agonist, endogenous agonist APA and M B A and |
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| 00:41 | And we also said that pharmacologically, can be distinguished by their own specific |
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| 00:48 | agonous uh synthetic or natural in this , synthetic. So the major difference |
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| 00:55 | that we talked about between abu and A receptors. And in general, |
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| 01:00 | going to be responsible for the E S P with the excitatory potential |
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| 01:07 | And the early part of this potential mostly due to a receptor activation. |
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| 01:16 | the last and prolonged part of this is mostly due to an MD A |
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| 01:23 | activation. So the reason for it because once glutamate is released it binds |
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| 01:31 | alpha and an MD A receptor alpha open up immediately and MD A receptor |
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| 01:37 | not because an MD A receptor have magnesium block. And the only way |
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| 01:42 | remove the magnesium block would be to the plasma membrane above the resting membrane |
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| 01:49 | . And that depolarization has been done the initial influx of sodium ions through |
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| 01:56 | amper receptor channels and subsequently opening an A receptor channels and continuing with the |
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| 02:03 | portion of the E P S So As far as conductance is not |
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| 02:11 | MDA or amp receptors will conduct about PICO semen and an MD a receptor |
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| 02:17 | conduct about 50 cements. Uh and have their own distinctive blockers or |
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| 02:25 | So ample is blocked by ce Q and MD A by A P D |
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| 02:31 | MD A is referred to as coincident because it actually has to presynaptic, |
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| 02:39 | the binding of glutamate. But also has to detect posy de depolarization which |
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| 02:45 | through the activation of ample receptors. addition to glutamate binding to an MD |
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| 02:51 | receptor. Glycine and the C N is a co factor that is necessary |
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| 02:57 | this MD A receptor to properly So, glutamate and glycine both have |
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| 03:02 | bind and once they do and once is depolarization, they alleviate magnesium blocked |
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| 03:10 | allow more influx of sodium and calcium and influx of potassium ions. And |
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| 03:17 | there are multiple binding sides for endogenous , multiple binding sides for ions where |
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| 03:25 | can insert themselves into the little cook uh uh of, of uh little |
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| 03:31 | of the proteins and block the protein . And there are also exogenous illicit |
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| 03:40 | . Uh We talked about PC you mentioned at least angel dust and |
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| 03:45 | terms and illicit drug that has very binding properties within the sector and can |
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| 03:51 | significant psychosis related and schizophrenia related even problems following a single use. The |
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| 03:58 | is that a lot of the substances are natural uh are partial agonist and |
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| 04:03 | will bind to these receptors and they part partially only partly uh open or |
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| 04:10 | or antagonize. They can be antagonist . But a lot of chemicals may |
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| 04:16 | binding through these re in much stronger . And if they bind them in |
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| 04:20 | stronger fashion, they be they can there for two weeks causing whatever effect |
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| 04:26 | psychosis like behavior until there is a of that molecule from the receptor. |
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| 04:35 | this is still all an atropic signaling metabotropic signaling glutamate will activate metabotropic glutamate |
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| 04:43 | . And there is a whole uh for metabotropic glutamate receptor will review in |
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| 04:48 | little bit. But let's go back some of the things that we learned |
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| 04:53 | the first portion of this course. you remember we talked about voltage |
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| 04:57 | OK. And voltage clamp allowed us hold the plant, the potential of |
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| 05:02 | desired value minus 60 minus 30 0 30 plus 60. And we said |
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| 05:09 | reason why you want to hold the potential at different Values, which are |
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| 05:16 | values, experimental values that you said can set it the -62. If |
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| 05:20 | want to, you can set it as a matter. The reason why |
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| 05:23 | because you want to isolate individual currents voltage clamp was very useful to isolate |
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| 05:31 | inward sodium currents during the action initial phase and the outward potassium currents |
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| 05:38 | the following phase of the action Right? Everybody is with me. |
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| 05:43 | remembers that everybody remembers uh I V and equilibrium potentials or reversal potentials. |
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| 05:55 | in this case, we're gonna look two experimental conditions in which on the |
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| 06:01 | you have normal physiological level of magnesium is 1.2 milli molar. And on |
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| 06:09 | right, you remove that magnesium, experimental condition, but you remove that |
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| 06:15 | from the extracellular solution. So there's magnesium on the right, you apply |
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| 06:23 | and you're looking at specifically an MD receptor current activation. And would you |
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| 06:31 | that in normal concentrations of magnesium which block an MD A receptor magnesium. |
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| 06:40 | . Normal concentrations with minus 60 you see much of the current flux. |
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| 06:45 | this line here there are some little if minus 30 you see more prominent |
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| 06:52 | flux through an MD A receptor. that just confirms that. Yes, |
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| 06:58 | need to have depolarization, not just . In order to see an MD |
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| 07:04 | receptor activation, you have to have . This experiment also showed that the |
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| 07:11 | potential in this case, it's not potential, equilibrium potential was E I |
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| 07:20 | and that was for a single ionic such as E K plus. For |
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| 07:26 | , for potassium, when we talk these receptor channels, we already discussed |
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| 07:33 | these receptor channels are not selective to I am, right? So we |
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| 07:41 | give just value based on ion. is actually allowing for the influx of |
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| 07:49 | calcium Tassi. Each one has their equilibrium potential values ionic. But what |
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| 07:58 | the combination and different receptor channels will prefer to conduct certain rates of ions |
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| 08:05 | word versus certain rates of ions And so what this shows is that |
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| 08:11 | millivolts there, there's a reversal of NBA current, A positive 30 and |
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| 08:19 | 60. There's significant current fluxing. significant deflections from this electrode recording line |
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| 08:28 | on the right where the magnesium is and glutamate is released. So it's |
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| 08:34 | the presence of glutamate on the What you're seeing is that if there |
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| 08:40 | no magnesium zero magnesium, then glutamate enough to open an MD eight channels |
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| 08:46 | the significant current flux of minus 60 minus 30 still reverses at zero. |
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| 08:53 | there is more significant flux even in more positive holding potentials. OK. |
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| 09:01 | is that clear voltage cloud recording an A receptor currents? Those currents are |
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| 09:09 | ionic currents. We're not talking about potential. We're talking about reversal |
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| 09:15 | Why is this reversal potential? Because card, you see these deflections from |
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| 09:21 | line going downwards and then on the side, you see the deflection going |
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| 09:27 | , the current direction reverses OK. it's inward, inward, inward, |
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| 09:34 | and it's zero, there's no current the positive holding becomes it becomes |
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| 09:41 | Yes. So just so I understand the magnesium is removed, um At |
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| 09:50 | is not removed at negative 60 magnesium gets removed if you have depolarization |
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| 09:55 | ample receptor first. OK. Uh let's talk about this experiment. If |
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| 10:07 | understood the previous experiment, voltage OK. Recall these plots. This |
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| 10:18 | current, this is mill called these I V plots. There was a |
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| 10:25 | on exam one on, on I plots linear I V plot right where |
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| 10:33 | will have reversal of sodium current of current. So this is an experiment |
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| 10:43 | you're holding a different potential here with clamp minus 80 minus 40 positive 20 |
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| 10:53 | , you're holding it and then you stimulating. So this artifact, this |
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| 10:59 | line here is a stimulus and that you can imagine is glutamate, let's |
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| 11:04 | or stimulation of glutamate axons. And you're gonna take two measurements. The |
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| 11:12 | measurement here is the first dash line is the peak early component, a |
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| 11:21 | current and you can see that the current actually occurs. This is 50 |
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| 11:28 | within about five milliseconds of the start these excitatory currents. And the second |
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| 11:38 | that you're doing here is the second line. But the second dotted line |
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| 11:45 | can see is measuring the amount of following the stimulation about 40 milliseconds or |
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| 11:53 | later. So you're measuring the two points, the early time point. |
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| 12:00 | me, you're measuring the amplitude of current here and you're measuring the amplitude |
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| 12:04 | the current here, 40 milliseconds So when you're taking the measurements from |
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| 12:11 | early component, you're actually taking information is related to ample receptor because it's |
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| 12:22 | for the early component of the E S P. So this linear I |
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| 12:28 | plot in either closed or open triangles a receptor cards. If you have |
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| 12:40 | apa receptors are gonna be open at holding potentials at resting membrane potential of |
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| 12:47 | -65, all of this is a . So you can see significant amp |
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| 12:54 | and resting membrane potential because you're releasing . And this early component is this |
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| 13:01 | the early component where you're taking the and you get this linear I V |
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| 13:07 | and that's the APA receptor. So receptor channel has a linear I V |
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| 13:15 | with the reversal potential of zero And so it turns out that E |
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| 13:23 | S D and E P P which generated by Cey coline or glug currents |
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| 13:34 | colergic currents through nicotinic acetal colon This is also ionotropic currents, glug |
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| 13:43 | , right. They all have a potential, not ionic but e reversal |
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| 13:50 | of zero millivolts E P S P MD A receptors, APA receptors, |
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| 14:03 | acetylcholine receptors and plaid potentials that all nicotinic acetylcholine which mediates plaid pool will |
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| 14:14 | have a reversal pool that zero So the excitatory signaling seems to reverse |
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| 14:21 | at zero millivolts. And the alpha channel has a linear I V |
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| 14:30 | Now, when you trace the second here at minus 80 when you release |
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| 14:36 | , you take a measurement here and is very minimal current deflection here that |
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| 14:44 | can observe. OK. So you're from this is your baseline here and |
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| 14:49 | baseline, you mean measuring to P and then the late component, you |
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| 14:54 | measuring from the same baseline and you see a very small deflection that's left |
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| 15:02 | . And you can see that this area under the curve is an MD |
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| 15:08 | receptor component that is responsible for the component of the E P S |
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| 15:15 | And in this case, the, closed circles, the plot for the |
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| 15:21 | circles is the plot for the late MD A for late current and MD |
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| 15:28 | receptors where there is this is current , there's very minimal current at negative |
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| 15:34 | , it's resting number and potential. then when you depolarize the number in |
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| 15:41 | , there is significant current through an A receptor, it also has a |
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| 15:46 | potential and then it conducts again in opposite direction awkwardly. So an MD |
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| 15:53 | receptor channel currents on the late component a nonlinear I V plot unlike APA |
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| 16:03 | . And the final iteration here experimentally that we applied A P D and |
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| 16:09 | showed you in the previous slides and time mentioned that A PV is a |
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| 16:17 | blocker for an MD A receptor. if you applied a PV and it's |
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| 16:22 | for an MD A receptor, do think there should be an effect on |
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| 16:26 | early ample component? If you apply blocker for an MD A receptor, |
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| 16:35 | you think that's going to affect the alpha component? No, thank |
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| 16:41 | So, so you will not affect component. So this is peak early |
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| 16:47 | , not an MD A receptor. triangles and open triangles are identical in |
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| 16:53 | presence or absence of this A P , it doesn't affect this linear |
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| 16:58 | Now, if you applied a molecule specific antagonist, A P D one |
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| 17:03 | D receptor and you just recorded this curve, what would you expect would |
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| 17:08 | to the late component? It would blocked and when that late component is |
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| 17:14 | , you would get this nearly straight , there's almost nothing completely in in |
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| 17:21 | that's zero or a complete straight But these open circles would indicate an |
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| 17:26 | A re up to current in the of a PV blocker which again confirms |
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| 17:31 | this is pharmacology, neuropharmacology, agonous , voltage clamp, just like we |
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| 17:39 | talking about it about action potentials. so you have this early component that's |
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| 17:45 | , a linear, it's not affected an MD A receptor blocker. This |
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| 17:50 | component is nonlinear here, it's an . It is completely blocked by A |
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| 17:56 | , which is specific an MDA receptor . And when you block a, |
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| 18:01 | MD, you would be blocking this area under the curve, which essentially |
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| 18:07 | what an MD recor has contributed to post synaptic current depolarization. OK. |
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| 18:16 | now there's a couple of other interesting to discuss about glutamate signaling. You |
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| 18:24 | calcium permeability only in some ample So we discussed that N MD A |
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| 18:32 | will all be permeable to sodium calcium potassium, but only some APA receptors |
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| 18:39 | be permeable to calcium. And it out that if you take this |
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| 18:49 | this protein here, it has the one M two M, three M |
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| 18:56 | segments within M two segment. There an amino acid. Remember that this |
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| 19:04 | a portion of the protein that we're into here, right? And we're |
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| 19:10 | into a specific area with an M2 transmembrane subunit here. OK. And |
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| 19:20 | that all of these subunits are amino , they've been twisted and the hexes |
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| 19:28 | into the transmembrane segments and so And so there is Q which stands |
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| 19:33 | glutamine and APA receptors are you're gonna able to allow for calcium to influx |
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| 19:41 | . But in some versions, edited , Q gets replaced with arginine R |
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| 19:50 | there is no calcium flux through APA channels. So I imagine how specific |
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| 19:58 | is that you have this again, complex three dimensional protein structure which is |
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| 20:03 | receptor channel with different binding sides, complex architecture subunits interacting with each other |
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| 20:12 | this channel. But you change one acid and it's significant because influx of |
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| 20:20 | and a source of calcium poop is necessarily as much for depolarization of the |
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| 20:25 | membranes as influencing the secondary messenger and cellular mechanisms. And so this experiment |
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| 20:35 | we applied glutamate 300 micro molar glutamate we isolated the voltage plant and we're |
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| 20:42 | sodium current. And in this Q which is glutamine, you have sodium |
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| 20:50 | and you apply glutamate and you isolate current with voltage club and you have |
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| 20:56 | . But then you have R which the arginine, you apply glutamate, |
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| 21:02 | still have sodium carbs. So it's like that channel that has one amino |
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| 21:08 | substitution is no longer permeable for ions . It's just not permeable to calcium |
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| 21:14 | now you still have sodium carbs, calcium is a flat line essentially. |
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| 21:20 | . There's no calcium carbs ontogeny is distinguishing factor in the formation of the |
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| 21:30 | liar signaling is that early on in synopsis, we find only in MD |
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| 21:38 | receptors and because we only find an A receptor releasing glutamate, that those |
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| 21:45 | may be quite ineffective. Why? in order for an MD A receptor |
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| 21:52 | be functional, you have to have coming from APA receptors. So in |
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| 21:57 | absence of APA receptors, glutamate can released. But an MD A receptor |
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| 22:03 | are not going to open. So uh synapses are referred to as silent |
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| 22:11 | silence synapses because there's still chemical neural , there's glug transmission, but an |
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| 22:19 | A receptor channels don't open and there's levels of activation, very intense levels |
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| 22:27 | activation that are typically calcium mediated developmentally will open and allow for the opening |
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| 22:34 | these receptors. And MD A receptors also comprised of subunits. Those are |
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| 22:39 | to an MD A receptor subunit. N R two subunit, N R |
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| 22:45 | A and R two B is an subunit in an MD A receptor because |
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| 22:51 | composition and the ratio of N R A to N R two B shifts |
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| 22:57 | the development. So you have these or five different subunits that make up |
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| 23:06 | channels, but you can switch them into different subtype of subunits. So |
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| 23:12 | can have an R two A S N R two BS and an N |
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| 23:15 | two A can be dominant early on later on. You look at the |
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| 23:21 | A receptor and they're dominated by these R two B subunits which have slightly |
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| 23:26 | structures and therefore influence the function of receptor channels, cellular location and activity |
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| 23:37 | , cellular location. It it, course, amp and MD A receptors |
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| 23:41 | be subcellular. Where would you locate ? You would locate them in the |
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| 23:47 | in the posy tic densities in the and also in the inhibitory cells. |
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| 23:53 | you'll have glutamate receptors on the excitatory inhibitory cells on both. There are |
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| 24:01 | of these receptors and apa receptors when open. And if you recall the |
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| 24:09 | membrane is a fluid mosaic model, means that substances within this fossil lipid |
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| 24:16 | , they're not static. They can through the fossil lipid bilayer space. |
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| 24:22 | a lot of channels, receptor channels are located in the extra synoptic spaces |
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| 24:29 | the synopsis. And now we learned with activity, you can actually induce |
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| 24:36 | receptors coming into the synopsis. So the extra synoptic spaces, they're not |
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| 24:42 | receiving glutamate, they're not functional. once the synopsis become very active with |
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| 24:48 | , it can call upon the extra protein receptor channel reserves to import them |
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| 24:54 | the synapses and help with this excited glutamate signaling. And if you change |
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| 25:01 | signaling and the strength of signaling, are now talking about synaptic plasticity, |
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| 25:09 | changing the efficacy or the signaling. there's this term here. Abbreviation L |
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| 25:16 | P some of these changes can be lasting changes. And these changes in |
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| 25:24 | signaling between the cells is an activity process. It's a sensory activity dependent |
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| 25:31 | too. How your circuits develop, preference? Even sometimes what talents you |
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| 25:37 | . A lot of time comes of , from some genetic component, but |
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| 25:41 | environmental component that you're exposed to. if you're exposed to certain things, |
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| 25:49 | synapses that are learning those things are , you have plasticity. And one |
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| 25:55 | that you can strengthen the synopsis is the excitatory signaling and through import of |
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| 26:02 | excitatory receptor channels, make it really , make it really communicative to the |
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| 26:08 | synoptic side. The long term plasticity L T P is something that can |
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| 26:14 | induced. And when it gets induced when you have the changes and the |
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| 26:19 | of new receptors of the plasma membrane the level of the synapse or import |
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| 26:25 | the extra synaptic spaces. Both A B A Kate. Also the third |
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| 26:32 | are inotropic glutamate receptor. This is metabotropic glutamate receptor. This is one |
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| 26:38 | the signaling cascades of metabotropic glutamate In fact, many different subtypes of |
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| 26:45 | glutamate receptor and blue are 12345, the way I believe through 12. |
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| 26:50 | means that there's something different about their . The sequence of the amino acids |
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| 26:55 | are ultimately affects the function and that's they are different subtypes of metabotropic in |
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| 27:02 | case glutamate receptor. This is an of metabotropic glutamate receptor coupled to G |
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| 27:09 | . And it converts P IP two through phospho I PC P L C |
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| 27:17 | IP three or annoy triphosphate and into glycerol annoy triphosphate can bind to smoothen |
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| 27:28 | plasm reticulum calcium receptor channel. So anty phosphate IP three binds to these |
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| 27:38 | , there are also calcium channels that for slut and the plasma particulate to |
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| 27:44 | a lot of calcium into cytoplasmic Recall that calcium is not gonna be |
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| 27:51 | significant for depolarization of the plasma Then calcium is going to be very |
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| 27:56 | for this postsynaptic cellular function or activating messengers. In fact, calcium molecule |
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| 28:04 | is a secondary messenger also. So the other hand, you have a |
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| 28:10 | that remains membrane bound and that's D G which is diacylglycerol and that can |
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| 28:17 | protein K AC or P K And so we already mentioned, but |
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| 28:24 | of the Kis and phospho AIS are significant. So well postulate the |
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| 28:36 | OK. four proteins that will add P 04 group. OK. And |
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| 28:48 | will take it away, we'll chew off and despoil it and force correlation |
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| 28:56 | dephosphorylation is important uh way of regulating modulating ionic channels receptors, sometimes even |
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| 29:08 | G protein coupled receptors. So, of KIS and phosphates is the |
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| 29:15 | expression levels of KIS versus phosphates are important and cellular activity levels, it's |
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| 29:26 | lasting effects. The release of calcium very important for activation of calcium interacting |
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| 29:34 | such as calcium co module knas is one of the knas just like protein |
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| 29:41 | also. OK. So we talked uh glutamate and we talked about in |
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| 29:53 | about the ionotropic an M MD A K and these are ionotropic, |
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| 30:11 | So this is glutamate, right? this is ionotropic. Now, we |
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| 30:22 | talked about metabotropic glutamate receptors and these metro and we said that ionotropic signaling |
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| 30:39 | glutamate contributes to neuronal membrane potential changes . It's very important for E P |
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| 30:45 | P or depolarization, synoptic ionotropic And we talked about how metabotropic signaling |
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| 30:57 | in glutamate is important for Calcium regulation , phosphorus regulation, cellular activity |
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| 31:08 | transcription factor downstream all of these phosphorylation of molecules, right? So |
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| 31:14 | not really talking about EPSPIPSP- one. talking about metabotropic glutamate receptor. |
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| 31:21 | Let's move into, yeah, which for gamma immuno butyric acid Gaba and |
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| 31:39 | . When Gabba binds, there are types of Gaba receptors for ionotropic, |
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| 31:46 | is Gaba A the metabotropic, there Gaba B and on TV, there's |
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| 31:56 | , Gaba, I always like Uh that show actually uh it's, |
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| 32:02 | , it's quite, quite entertaining. Gaba A and Gaba B. So |
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| 32:07 | we're talking, this is of excitatory signaling and may, right? |
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| 32:14 | you're talking about isotropic signaling, you're about B P SPS. What about |
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| 32:20 | . Is there is there depolarization, you depolarize the south more from me |
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| 32:25 | ? I know you're not talking about P SPS here. But can you |
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| 32:29 | because you said you can phosphate right? And open certain channels and |
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| 32:34 | certain channels? Right. So is an effect there? And you know |
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| 32:39 | what is the fact? So if activate metro glutamate receptors, is it |
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| 32:44 | be uh always a depolarization on the downstream from metro glutamate receptors? And |
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| 32:51 | answer is actually a mixed bag of . It just depends on the receptor |
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| 32:57 | the type of cell that you're OK. So and as far as |
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| 33:01 | charge change you have here, definitely . And here you also have something |
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| 33:08 | minimal. So when you're talking about charge, OK, this is |
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| 33:14 | you have a minimal change of that as it relates to metabotropic signal. |
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| 33:22 | one if that happens, minimal that minimal charge could influence the cell |
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| 33:28 | be slightly more depolarized through one metabotropic receptor and one signaling cascade or it |
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| 33:36 | cause it to be slightly hyper polarized another metabotropic receptor through another signaling cascade |
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| 33:41 | yet another effect on another ionic All right. So now, when |
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| 33:49 | binds to Gabba A receptors, Gabba receptors allow for the influx of |
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| 33:57 | And when chloride influxes chloride influxes, is responsible for hyper polarizing the |
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| 34:07 | And this initial hyper polarization is due GA B component. And this is |
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| 34:16 | chloride, Gaba gated chloride channels or chloride is going to enter into the |
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| 34:24 | . Why is chloride entering into the ? So there's a lot of sodium |
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| 34:27 | on the outside of the cell it cause and it will be responsible for |
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| 34:36 | . OK. And it's going to responsible here for the IP S |
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| 34:42 | not E P S P, but S P. And here when we |
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| 34:47 | at glutamate, we talked about E S P excitatory poop potential. When |
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| 34:55 | looking here at Gava, we're talking IP SPS, inhibitory poop potentials. |
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| 35:03 | A receptor has other binding sides to just like an MD A receptor. |
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| 35:08 | we said that you can have binding for glutamate for glycine. There's a |
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| 35:13 | side for a PV because it's an . There's a binding side for magnesium |
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| 35:19 | an MD A receptor. So look the Gabba a receptor binding sides |
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| 35:26 | It's almost the weekend ethanol binds to A receptors and increase its influx of |
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| 35:37 | , right? So happy hour is activation of ethanol and there's a little |
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| 35:44 | of inhibition at the beginning with one depending on your tolerance level, but |
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| 35:52 | lose that inhibition. After three or , there is disinhibition that happens. |
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| 35:57 | a whole process behind it. We get into the details. But |
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| 36:01 | so ethanol binds to Gabba A. ? What does it do eventually if |
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| 36:06 | you, if you activate it enough , you're really sedated, you first |
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| 36:13 | on the table but then you're, know, really, really sedated. |
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| 36:18 | next stage you see Benzodiazepines. So you turn on the radio channels, |
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| 36:25 | know, you will hear Benzos and songs about Benzos. So, Benzodiazepines |
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| 36:33 | pharmaceutical medications. You know, everything abused in different markets and by different |
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| 36:40 | . But Benzodiazepine is a very classical anti seizure, anti epilepsy medication. |
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| 36:51 | does it do? It sedates How does it make people feel similar |
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| 36:59 | being drunk? Why? Because it's same target receptor. We talked about |
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| 37:06 | cannabinoids and and, and and endo like an Andam will activate C B |
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| 37:11 | receptor and cause the euphoria feeling the high phyto cannabinoids like delta nine T |
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| 37:16 | C will also activate C B one and cause a different type of hyo |
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| 37:22 | . So here again, it's the target. So you can expect a |
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| 37:27 | effect from those medications that you would from consumption of alcohol. And it |
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| 37:32 | true. People that take high concentrations benzodiazepines, they seem almost like drunk |
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| 37:39 | to, to losing their gate and problem. You also have their bitch |
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| 37:44 | there are steroids that will bind to Gabba eight channel. Now this is |
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| 37:50 | another example of multiple substances, multiple sides, all of these molecules that |
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| 38:01 | talking about. They're agonists, So Gaba will open chloride channel benzodiazepines |
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| 38:08 | open chloride channel, ethanol will open channel. An influx of chloride causes |
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| 38:14 | . It causes hyper polarization. That's they're sedative. That's why they're antiepileptic |
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| 38:21 | that act through the Gaba A receptor . We also have Gaba B receptor |
|
| 38:29 | it turns out that Gaba B receptor contributes quite significantly. So I'm gonna |
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| 38:37 | a check mark here, checkmark here only one checkmark here for charge. |
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| 38:43 | . So this is charge, love charge. So it turns out that |
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| 38:52 | B contributes quite significantly to the late portion of this IP S P. |
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| 39:01 | it also turns out that it does fast by opening potassium channels. You |
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| 39:08 | in a couple of yourself, you potassium channel positive charge of meeting the |
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| 39:11 | . What happens to the cell It gets more negative. So the |
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| 39:17 | initial component of IP S P is A and delayed component is Gamma B |
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| 39:25 | , however, is metro bop. it's different from apple and D A |
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| 39:29 | both on a tropic one was one was late. Now we're talking |
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| 39:34 | two very distinct Gabba A and Gaba components. The early and late IP |
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| 39:43 | presynaptic. Guess what? Gamma B protein coupled complex does it closes calcium |
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| 39:52 | , presyn optically voltage gated calcium Does that sound familiar endo cannabinoids, |
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| 39:58 | signaling closes voltage gated calcium channels regulates of neurotransmitters B, presynaptic. Whoa |
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| 40:07 | whoa, what does that mean? means that you have GB posy tic |
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| 40:11 | you have gabba b receptors presynaptic So now it also depends, not |
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| 40:17 | what sub type of receptor is expressed what synaptic side, but it also |
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| 40:22 | on what is located presynaptic. And poop, you can hyperpolarize the cells |
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| 40:28 | E P S P. And presynaptic receptors can control the release of exciting |
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| 40:36 | inhibit their neurotransmitters just like endo cannabinoids . And there is a redundancy here |
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| 40:42 | it's the same mechanism. C B receptor cannabinoid receptor activation with through G |
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| 40:47 | complex with block house and channels. what if you are missing the endocannabinoid |
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| 40:53 | C P one receptor function? It's but you have to regulate cal and |
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| 40:59 | have another backup system. Well, it is, it's got b there's |
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| 41:03 | redundancy then in how these systems can each other up through completely different receptor |
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| 41:11 | . But they converge and the cannabinoid B one receptor Gaba through Gaba G |
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| 41:17 | converge on these presyn and would regulate presynaptic calcium channels. This diagram puts |
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| 41:27 | in really great perspective. I really this diagram and let's look at what's |
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| 41:32 | on here. So first of if it says here, synoptic, |
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| 41:37 | releasing God, this is an inhibitory . Second of all, on |
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| 41:41 | you have glutamate releasing synapse. So is the excitatory synapse. So let's |
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| 41:47 | through this diagram. Now. So have this, you have a lot |
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| 41:52 | Gaba here on this side and inhibit synapse. And pontic you have Gabba |
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| 41:59 | . This is your key here. is your Gabba A receptor and blue |
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| 42:03 | A are permeable to chloride. And , you also have these little kind |
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| 42:10 | winged like receptors and these are G coupled gabba B metabotropic. OK. |
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| 42:18 | Gamba B are metabotropic, recall that metabotropic but they will open potassium |
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| 42:26 | So when Gaba gets released presyn, will bind to Gamba. A cause |
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| 42:31 | initial component of IP S P bind Gabba B with some delay, |
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| 42:38 | 20 milliseconds cause the late component of S P by opening these potassium channels |
|
| 42:46 | . OK. Everybody with me. it turns out I said, |
|
| 42:50 | wait a second. You also said there is will be presynaptic receptors chan |
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| 42:56 | I said, yeah, there is presynaptic receptors and they will modulate calcium |
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| 43:02 | . So these gabba releasing neurons pre terminals on its own pre synoptic side |
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| 43:09 | have Gaba view receptors. And those view through the G protein comp complex |
|
| 43:16 | shut down the call influx. And you shut down the presynaptic calcium |
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| 43:23 | you can now shut down the release gain because these are Gabba B receptors |
|
| 43:31 | are located on the Gabba synapses that referred to as auto receptors. So |
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| 43:36 | synapse releases Gabba and at presynaptic, can also bind to the same synapse |
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| 43:42 | , which is an auto receptor All . OK. Next door, we |
|
| 43:49 | a glutamate synapse. Remember neurons pontic . This neuron po synoptic uh can |
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| 43:55 | an excited or a neuron or but they're a neuron. OK? |
|
| 44:01 | presyn tally if you're releasing gabble you neuron presyn if you're releasing glutamate, |
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| 44:07 | means you're synthesizing glutamate. That means exci posy, you can have glutamate |
|
| 44:14 | and MD A here and yellow. posy. That's excitatory synapse. |
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| 44:23 | synoptic you have gabba A gabba you have an inhibitory synapse here. |
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| 44:29 | this neuron that has an excitatory input and inhibitory input this poop neuron |
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| 44:37 | It can be either releasing GB or . So this synaptic neuron can be |
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| 44:45 | excitatory inhibitor. Let's look over next here. We have glutamate. So |
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| 44:50 | is excitatory synopsis. If we activate MD A receptor, there's going to |
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| 44:54 | significant influx of calcium. We said is calcium binding to calcium com com |
|
| 44:59 | K AIS. And it turns out these knees can activate Gala B receptors |
|
| 45:06 | they can also influence potassium channels posy . And guess what happens if you |
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| 45:14 | postsynaptic channels, these potassium channels through B or through the intracellular signaling |
|
| 45:22 | Potassium leaves you cause hyper polarization and can essentially shut down an MD A |
|
| 45:32 | channel. An MD A receptor channel depolarization. So it comes from |
|
| 45:37 | but if you now open potassium channel counteracts these depolarizations through gamma B, |
|
| 45:44 | can now influence that influx of uh uh uh and, and the function |
|
| 45:49 | an MD A receptor. In excitatory presynaptic terminals or excitatory uh cells |
|
| 45:59 | also contain GB receptors, pre But they're dubbed as gabba B heteros |
|
| 46:08 | because they're on other synapses. this synapse doesn't release, this, |
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| 46:13 | terminal doesn't release gama. But if is a lot of gabba in the |
|
| 46:18 | and it spills over, it can presynaptic Gabba B receptors on the glutamate |
|
| 46:26 | and can control the release of So now we see an example how |
|
| 46:32 | B, um Gabba releasing cells will the release of Gaba and how Gabba |
|
| 46:41 | heteros on exci glug cells through control calcium will control the release of |
|
| 46:51 | Mhm So again, this is one the diagrams that I would use intensely |
|
| 46:58 | the exam for studying or the But taking the notes, there's a |
|
| 47:04 | of things in here. There's a of great stuff in the figure |
|
| 47:07 | But if you don't understand what IP P or Gaba B is and things |
|
| 47:13 | that, you're in trouble. So this, use this as a great |
|
| 47:17 | guide uh and mark as much information as you possibly can. This is |
|
| 47:24 | example of a recording where you have stimulation here. This artifact is a |
|
| 47:33 | and the first thing you see is here. So this is an E |
|
| 47:37 | S P. So this is an of a compound E P S P |
|
| 47:45 | by IP S P. And so it shows you is that if you |
|
| 47:50 | the cells and they have this exci E P S P inputs, those |
|
| 47:55 | can also get immediately inhibited by A, the early component of IP |
|
| 48:00 | P and Gaba B, the late of IP S P. Now, |
|
| 48:05 | this C, I'm not gonna bore with the entire figure but in this |
|
| 48:10 | so we just discussed a all So weak stimulus E P S P |
|
| 48:18 | by inhibition, strong stimulus to get depolarization. Also, here you have |
|
| 48:24 | P S P followed by IP S . Bicuculline is a specific Gabo receptor |
|
| 48:32 | . So if in the presence, you apply bicuculline in the presence of |
|
| 48:37 | is a trace two. It's the stimulation as a number one. In |
|
| 48:42 | one, you stimulate, you get depolarization posy followed by an IP S |
|
| 48:48 | . But if you block the a component, this early component, |
|
| 48:52 | depolarization becomes very significant. So that you that inhibition and these inhibitory Gabba |
|
| 48:59 | and Gala B inputs really control excitability the synaptic cells. How much are |
|
| 49:06 | depolarized? And if you block you can get abnormal depolarization with even |
|
| 49:12 | potentials where they shouldn't be in normal . The G proteins a little bit |
|
| 49:19 | their structure. There are seven transmembrane , 1234567, there are spanning alpha |
|
| 49:29 | that are coupled to these G protein that will have their individual subunits, |
|
| 49:35 | beta gamma subunits of the G protein . They can be G S or |
|
| 49:41 | G I or inhibitory G Q for . And their functions are different depending |
|
| 49:48 | what receptor channel. They're tied to receptor, they're tied to what channel |
|
| 49:54 | or what molecule inside the cell. may be activating some G protein couple |
|
| 50:02 | transmitter receptors. So when we talk acetylcholine, we talked about how acetylcholine |
|
| 50:07 | have metabotropic receptors. They are And it turns out there's multiple subtypes |
|
| 50:15 | 123456 plus glutamate, a lot of gabba gabba B receptor, one gabba |
|
| 50:23 | receptor, two different subtypes of these , dopamine Norine will have their own |
|
| 50:30 | protein coupled receptors and keen uh CV one and CV two A T |
|
| 50:40 | or denison tristate, which will be through a denison receptors and also P |
|
| 50:46 | Y receptors that are quite specific for T P. But uh also we |
|
| 50:52 | that amino acids, glutamate Gaba and will act on a tropic and tropic |
|
| 51:02 | all the other uh molecules are seeing . They'll be acting through G protein |
|
| 51:10 | systems only solely through those systems. the transmitter gated channel structure. In |
|
| 51:16 | case is acetyl Cole which shows we just looked at these four uh |
|
| 51:21 | uh segments M one through M two 34. But we looked at it |
|
| 51:29 | the park receptor configuration, this is but it shows you alpha beta gamma |
|
| 51:38 | . So you have five subunits of acey cole receptor channel. These are |
|
| 51:44 | two binding sides. So two molecules to bind acetycholine molecules and to open |
|
| 51:50 | uh channel. OK. And this what I was telling you the composition |
|
| 51:55 | these subunits may shift. So instead having two alpha, there might be |
|
| 52:00 | delta and there's gonna be a slightly subtype of uh nicotinic acetylcholine receptor. |
|
| 52:07 | ionotropic uh receptors will also have their distinct subtypes. Uh So there are |
|
| 52:17 | , all of the ace in the , a Glycine kate, you can |
|
| 52:22 | that they will have this kind of one through M four transmembrane segment uh |
|
| 52:33 | . OK. So this is a I already talked about this a little |
|
| 52:36 | . What do you need to know this? Everything about acetyl coline? |
|
| 52:40 | sure, we drilled it enough. alpha beta. You should know that |
|
| 52:46 | have the push pull mechanism there. will be pulling the system away and |
|
| 52:52 | will be pushing the system to the of cyclic A MP that competing metabotropic |
|
| 52:58 | inside the cell glutamate al and MD and their agonist and antagonists for |
|
| 53:06 | You should know Gale A Gabba we discuss this and you should know |
|
| 53:10 | as an antagonist for Gabba B and T P will bind to P two |
|
| 53:16 | A T P recept that's very A type receptors also an adenine |
|
| 53:22 | So a type receptor subtype agonist. can see that this is a natural |
|
| 53:30 | neuro transmitter like A T P or and these are exogenous molecules. So |
|
| 53:38 | agonist and antagonist. So, adenosine here is an agonist for aide |
|
| 53:46 | You could be receptor and caffeine, we consider is an antagonist for a |
|
| 53:53 | that we should know if you use some unit analysis and look at this |
|
| 53:59 | combinations. You have also different subtypes alpha and beta sub units and gamma |
|
| 54:06 | delta. And so you can play game and figure out how many different |
|
| 54:11 | of these subtypes of sub units. can put together to influence the functionality |
|
| 54:17 | uh o of signaling, whether it's or metro signaling. In general with |
|
| 54:24 | messengers, you have amplification within the , a single channel uh will conduct |
|
| 54:33 | a single channel if you open that . But if you bind to G |
|
| 54:38 | coupled receptor, that reception will be to several G proteins. These G |
|
| 54:44 | or one molecule, one subunit can several downstream of factors that uh uh |
|
| 54:51 | T P conversion and can influence production several F K A A molecules from |
|
| 54:57 | source source, one P K A influence the production of a lot of |
|
| 55:02 | A MP and protein and phosphorylation in case of potassium channel. So there's |
|
| 55:10 | through the system from one receptor that be coupled to multiple G proteins. |
|
| 55:16 | are activating multiple factors, multiple uh inside the cells. You can have |
|
| 55:25 | , you can have divergence. Divergence neurotransmitter will bind to three different subtypes |
|
| 55:32 | the receptors that subtype one subtype of receptor. For example, subtype two |
|
| 55:39 | actually diverge and activate three molecules downstream three effector systems. We call |
|
| 55:46 | you have convergence. So you can transmitter ABC binding to their respective receptor |
|
| 55:54 | and all converging on the same let's say through cyclic A MP, |
|
| 55:59 | saw convergence and nog alpha, nog , they converge into cyclic A |
|
| 56:07 | OK. Now, here you have streams and redundancies. So, transmitter |
|
| 56:14 | may activate a one and A Transmitter B may activate B receptor, |
|
| 56:20 | both transmitter A and A one receptor B receptor will target the same effector |
|
| 56:29 | three. So what happens if you a one receptor, you still, |
|
| 56:35 | you lose a one receptor, you be able to have an effect on |
|
| 56:40 | is factor three. But guess You have redundancy here through the receptor |
|
| 56:45 | it can influence the factor three in same manner. And so this is |
|
| 56:49 | mechanisms to have redundancy and overlap and that are in parallel and can be |
|
| 56:59 | convergent, divergent or redundant. Now, we're done with neural transmission |
|
| 57:07 | for the next uh five minutes or , I'm gonna launch into the C |
|
| 57:13 | S and I'm gonna finish a little earlier. I have to actually leave |
|
| 57:17 | here fairly fast and appreciate maybe if hold off your questions for the next |
|
| 57:24 | and you will know next week about quiz also, which is going to |
|
| 57:28 | on Friday. So next Monday or , you should be able to register |
|
| 57:33 | 10 minutes to take the quiz on before spring break. Now, let's |
|
| 57:40 | about the structure of the C N and now we're done with neural |
|
| 57:48 | Let's talk, step back, take bird's eye view. We're studying the |
|
| 57:55 | . We spend a lot of time the membrane biophysics, synapse E P |
|
| 58:00 | P IP S P, glutamatergic All of this, we're talking about |
|
| 58:05 | brain, we're talking about the C S. We look at different |
|
| 58:09 | brains, this is the size and lot. So humans know we don't |
|
| 58:15 | the largest brains. Dolphins have much brains, elephants of the largest |
|
| 58:22 | So the according to a phrenologist should the smartest because size, uh all |
|
| 58:29 | being equal should be an indicator of certain functional performance. So that's not |
|
| 58:34 | case. We're still at the top the food chain, at least on |
|
| 58:38 | , put us in the water. toasts. Dolphins will be our best |
|
| 58:43 | and smarter than us. Now, we look at this, uh, |
|
| 58:48 | to scale. We see a lot gross anatomical similarities between the brains. |
|
| 58:54 | we also see certain differences. If look at the lower species brains, |
|
| 59:00 | , rabbits, lizards, even lower , their brains are relatively smooth |
|
| 59:08 | There's even a a saying in the lizard brain which means a smooth |
|
| 59:12 | or you know, somebody that's not , uh, very well. So |
|
| 59:17 | you look at human brains that have lot of imaginations, the salsa and |
|
| 59:26 | gyri and this increases significantly the surface . So the size is not |
|
| 59:32 | but it's really the surface area. the complexity of the cellular subtypes in |
|
| 59:40 | mass. And also obviously the complexity the connectivity which can influence how we |
|
| 59:48 | things and how we think about things all of our motor actions, motor |
|
| 59:54 | . So when we talk about uh in general or the brain, we |
|
| 59:59 | to remind ourselves of some basic uh the nose or the front, |
|
| 60:05 | anterior is also rostral, the posterior also coal. This is dorsal, |
|
| 60:12 | back of the spinal cord, this ventral, the front of the spinal |
|
| 60:17 | , medial is in the middle of central, lateral is away. So |
|
| 60:22 | there is a medial nucleus, it gonna be closer to the center of |
|
| 60:25 | brain. Its lateral is gonna be to the lateral edges of the of |
|
| 60:30 | brain or a certain structure. And lot of times we study the brain |
|
| 60:36 | making sections and these sections can come different planes. It can be a |
|
| 60:40 | saal plane that that's sort of a the middle, from midline, laterally |
|
| 60:46 | laterally to middle line, the laterally horizontal, which goes essentially from |
|
| 60:53 | uh dorsal in this case, all way down and coronal which will be |
|
| 61:01 | sections across the brain. And when is called, you're looking at the |
|
| 61:06 | section from this animal in this region the frontal lobe region, then we |
|
| 61:12 | to see a certain anatomy, a display certain map of maybe go or |
|
| 61:17 | like this that we can recognize. OK. Uh Now you can see |
|
| 61:23 | obviously we have right hemisphere, left uh responsible for slightly different functions. |
|
| 61:31 | saw that lateralization, localization, specific of parts and also lateralization or the |
|
| 61:38 | areas on the left side. For . Now you can have the the |
|
| 61:43 | stem and the spinal cord. This a view cut, exposing the rodent |
|
| 61:49 | , the rodent brain. You can that there's no virtually no band Between |
|
| 61:54 | brain and the spinal cord in We have this almost 90° bend from |
|
| 61:59 | brain into the brain. So there's spinal cord going into our vertebral |
|
| 62:06 | So we have cerebral cerebral hemispheres. cerebral hemispheres will process information, |
|
| 62:13 | information, contralateral, right, left and left will command the right hand |
|
| 62:22 | will also be contralateral. So this from cerebra ok, from cerebral |
|
| 62:29 | When we talk about cerebellum and we about motion control cerebellum will be controlling |
|
| 62:36 | on the same side. So left will be controlling left side in |
|
| 62:41 | right will be controlling right. So different for cerebellum. Brain stem is |
|
| 62:47 | area is we have location of a of cerebro cera and cereal, |
|
| 62:58 | So if it originates in cerebral and to cerebellum, it's cerebral cerebella, |
|
| 63:03 | it originates in cerebellum, it goes cerebral, it's cerebella, cerebral. |
|
| 63:09 | , if it originates in spinal cord goes to cerebral, it's spinal cerebral |
|
| 63:15 | if it's uh from cortex into spinous . So the first word in these |
|
| 63:22 | corticospinal cerebral cerebella, the first word the origin from where the fibers or |
|
| 63:30 | inputs are originating. And the second is the destination of the target. |
|
| 63:35 | so you have both cerebral, talking cerebellum through brain stem and about and |
|
| 63:41 | back to cerebral through the brain So there's a lot of interconnecting fibers |
|
| 63:48 | in the brain stem, you also Nuclei that are responsible for vital body |
|
| 63:57 | such as breathing uh heart rate, control of body temperature and consciousness in |
|
| 64:05 | two. And we'll look into more about this. Again, when we |
|
| 64:11 | about peripheral nervous system, we have somatic voluntary motor and sensory, peripheral |
|
| 64:18 | system. So this is our projections go into the skins, joints and |
|
| 64:24 | , the motor neurons, and we'll talking about the uh somatic uh somatic |
|
| 64:29 | inputs going into the spinal cord from . And the visceral peral nervous system |
|
| 64:35 | autonomic nervous system. It's really, now they're kind of a very interesting |
|
| 64:41 | system that's associated with the internal blood vessels and glands. And there's |
|
| 64:47 | whole what we call mesenteric nervous And it, it's emerging at almost |
|
| 64:53 | complex the regulation of the digestive system digestive tracts and also what we have |
|
| 65:02 | our gut, the gut brain so to speak what we have in |
|
| 65:07 | gut and the microbiome, the microorganisms genetic material that we carry from different |
|
| 65:14 | and bacteria can influence through mesenteric nervous and through the metabolic activity in your |
|
| 65:20 | can influence your brain and vice Your brain and chemical functioning, the |
|
| 65:27 | can influence mesenteric nervous system, can the environment there and the microbiome of |
|
| 65:34 | environment. So there is a pretty gut brain axis and link that is |
|
| 65:40 | emerging. This last slide shows before get into the anatomy of the brain |
|
| 65:45 | the brain is fairly well protected. of all, we have this pretty |
|
| 65:48 | skull and it's hard to break. then underneath the skull, we have |
|
| 65:54 | thick dura mater. It's sort of like a really thick animal skin, |
|
| 65:59 | cannot tear it uh by hand, have to cut through it with a |
|
| 66:04 | or scalpel. So it, it's durable, hard mother or duma |
|
| 66:12 | You have some dual space which has rayo membrane is another type with the |
|
| 66:18 | here and on the very surface of tissue, brain tissue, you have |
|
| 66:25 | matter or the jungle matter here that and provides the nutritional support to the |
|
| 66:32 | tissue as well. Remember when we about the trepidations and we said that |
|
| 66:39 | tren nations were probably used as the neurosurgery to maybe alleviate the pain, |
|
| 66:47 | clean up the debris. So quite , if you have rupture of blood |
|
| 66:54 | , which would be innervating here, brain tissue and are located sub |
|
| 66:58 | sub sub, you can have a rupture of this blood vessel, let's |
|
| 67:03 | aneurysm, which is abnormal formation of blood vessel, thinning of the wall |
|
| 67:10 | of it. Now you're gonna have spilled all over here. And if |
|
| 67:14 | a small rupture, you're lucky. following a small blood rupture, you |
|
| 67:19 | have with coagulation, hardening that hardening coagulated blood is gonna start pushing on |
|
| 67:27 | tissue causing pressure and pain. The way that you can clean up this |
|
| 67:33 | is to do a trepidation and cut the duma and clean up the area |
|
| 67:40 | has been potentially wounded. And so have also dual hematoma. And if |
|
| 67:46 | don't clean it up, you can aggregation and formation and uh inflammation around |
|
| 67:52 | area of the injury, a vascular or another fluid formation that we'll see |
|
| 67:57 | can happen uh in hydrocephalus, for . Ok. So when we come |
|
| 68:02 | next week, we will be getting the development of the nervous system and |
|
| 68:07 | we will start talking about specific areas the brain and their functions. So |
|
| 68:12 | will learn a lot. Uh wishing a good weekend and uh remember your |
|
| 68:19 | receptors. |
|
