| 01:14 | About the neurotransmitter will be um influenced what subtype of the cell and how |
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| 01:24 | releases the neurotransmitter. In this the inhibitor neurotransmitter as well as the |
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| 01:28 | synaptic responses. So we already have how there is a great diversity in |
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| 01:33 | inhibitor into neurons and in particular, the functional, what I call dialect |
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| 01:42 | of these cells. So there's a variety of inhibitory interneurons. This is |
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| 01:48 | diversity of inhibitory interneurons and neocortex and very close proximity within the same patch |
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| 01:56 | neural network that here it doesn't have many cells. Maybe it has hundreds |
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| 02:00 | thousands of cells, you will find subtypes of neurons that will produce these |
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| 02:06 | frequencies of action potential, not only but also certain patterns of action |
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| 02:14 | And what we've learned last lecture, talked about the unitary EP SBS and |
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| 02:21 | talked about how a release or activation a single synapse and c single DeCicco |
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| 02:27 | in a small epsp. So if look at the pattern of these inhibitor |
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| 02:33 | , that pattern pre synaptic pattern of potentials will determine the presynaptic pattern of |
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| 02:42 | fusion and neurotransmitter release. And therefore posy pattern in the neuronal response. |
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| 02:50 | very simple terms. So this is presynaptic cell and this is postsynaptic |
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| 02:59 | And if we're reporting a pattern from po synaptic cell and the pattern in |
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| 03:05 | pre synaptic cell is something like this action potentials, it's very likely the |
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| 03:14 | that we're gonna report from the cell gonna look maybe something like this that |
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| 03:23 | essentially and it's a bad way to this. Maybe the best way to |
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| 03:29 | this like this. So this is be presynaptic or is that the sequences |
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| 03:38 | action photo Charles we would see. example, we said that that would |
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| 03:45 | , this is pre syllabic and this the apo synoptic. So, epsb |
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| 03:53 | example, this is excited for Now, if this is pre synaptic |
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| 04:01 | releases excitatory neurotransmitter, glutamate or it's gonna cause this pattern of up |
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| 04:10 | if we're gonna have presynaptic neurons and diversity of these presynaptic neurons. So |
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| 04:18 | is presynaptic inhibitor in neuron, a inhibitor in neuron B oh And these |
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| 04:35 | neurons inhibitory neurons are gonna produce a pattern of release of the neurotransmitter |
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| 04:44 | And let's say if this neuron a a pattern that looks like this versus |
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| 05:01 | B presynaptic neuron that produces a pattern looks like this as synaptic response that |
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| 05:16 | would record from the cell. So this is pretty, this is |
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| 05:22 | the likely postsynaptic response. One would from the South would be summation into |
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| 05:29 | really large depolarization. And here the response would look something like this |
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| 05:42 | So these would be, in this , I drew them wrong because those |
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| 05:49 | be hyper polarization. So if you Gaba or Synoptic, what we're going |
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| 05:57 | see are going to be hyper OK. And ply this is what |
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| 06:05 | was going to look like, for . So sorry for confusing you |
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| 06:13 | If you have a excitatory cell, have a certain pattern of presynaptic action |
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| 06:19 | . It means a certain pattern of responses, you have inhibitory cells. |
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| 06:25 | if you have diverse subtypes of these cells, that means that they're gonna |
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| 06:31 | very diverse patterns of the po synaptic SPS. And so these are IP |
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| 06:41 | , but these are EPSP. This how we study, we already talked |
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| 06:50 | the techniques that we studies inhibitory We have to have electrophysiology. Typically |
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| 06:58 | uh infrared microscopy. We have to morphology reconstructions of the cells. We |
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| 07:05 | to have something about cells, specific or their molecular profiles. And this |
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| 07:13 | neuron diversity is present in the hippocampus the circuit that we discussed at |
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| 07:20 | And this is how these cells vary all of these properties and features that |
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| 07:24 | just mentioned, but it's present in , it's also present in the spinal |
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| 07:31 | . So these are the inhibitory cells the spinal cord that have all of |
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| 07:37 | different firing, tonic firing, delay firing, single spiking and morphologically |
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| 07:46 | subtypes of the spinal cord inhibitory Ok. So th this diversity is |
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| 07:55 | throughout the C MS Neocortex hippocampus spinal and it contributes to very different |
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| 08:04 | not only pre synoptic action potentials, these very different bussy patterns that neurons |
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| 08:11 | be responding to and just recall. is from previous lectures that we have |
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| 08:17 | molecular tools, molecular analysis tools and . RN A sequencing S single cell |
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| 08:25 | that can reveal in the molecular profiles the different subtypes of cells. This |
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| 08:33 | another representation of when we look in in general on the circuit. It's |
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| 08:39 | representation of neurons that actually can be or disinhibitory or what is meant by |
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| 08:52 | . So for example, on this , we have cells that are gab |
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| 08:59 | interneurons that are disinhibitory. Those gabber are going to target other inhibitor into |
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| 09:10 | . So when this VIP vaso immuno and it's uh it's one of the |
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| 09:17 | markers VIP when this VIP positive Gaba because remember they're all Gaba cells, |
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| 09:24 | all release Gaba when this VIP Gaba releases Gaba on this somatostatin slm positive |
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| 09:33 | . The sonata statin cell, which turn has its synopsis on this parameter |
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| 09:40 | right here. The Sona Ain cell now disinhibited because it's the inhibition is |
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| 09:50 | and there is no, there's disinhibition the perimeter cell. Fetal cell is |
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| 09:55 | longer receiving inhibition. In the regular paradigm, you have these, for |
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| 10:03 | , Perin cells that we already mentioned the previous slides. If you look |
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| 10:09 | are Perin and positive cells like number , number four, these Perin positive |
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| 10:15 | inhibitory interneurons will release Gaba on the or or the dendrites of the peret |
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| 10:24 | . So they will inhibit parameter cells the inhibitor interneurons that will target other |
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| 10:31 | interneurons will actually cause disinhibition of para . So it's like two minuses equal |
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| 10:41 | a plus in in this case or or parameter. So it's we have |
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| 10:49 | yeah. So that is it's not excited, it's not excitatory signal, |
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| 10:58 | there is no no inhibition on the cells. Remember these are parameter projection |
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| 11:04 | . And so what happens is that certain this is like a a |
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| 11:11 | right? And these circuits, by way, a lot of times we |
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| 11:15 | to them as canonical circuits because this of signaling inhibition from into neurons versus |
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| 11:24 | . Those types of rules. This of signaling exists throughout different parts of |
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| 11:30 | brain, the cans neo cortex. there's some canonical circuits and canonical rules |
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| 11:36 | by which these cells in the cellular communicate with each other. And so |
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| 11:42 | certain amount of inhibition that is necessary control what these excited also are going |
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| 11:48 | project out and communicate to other And so there's constant sort of like |
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| 11:55 | balance your teetering between inhibition and And because they are targeting different parts |
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| 12:04 | the somo dendrites. And also because targeting each other and they have these |
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| 12:11 | patterns, it really now determines the of this output from the parameter |
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| 12:18 | not only the balance but also the of this output from the parameter |
|
| 12:24 | So I don't know if that completely your question. OK. Now that |
|
| 12:28 | other thing to look at in this is uh and uh again, you |
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| 12:35 | find this PDF in your folder. if not, I will upload |
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| 12:39 | maybe I didn't sync this one I'm not certain. But once you |
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| 12:44 | presynaptic neuron that uh releases uh there are, there's an important point |
|
| 12:53 | illustrated here. There are what we Gaba receptor channels that are located within |
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| 13:00 | synapse called synaptic receptors. But there some Gabo channels that are located outside |
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| 13:13 | the facilities and they're called extras. quite often when there is a little |
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| 13:19 | of Gaba release that Gaba that gets here is spatially fairly well confined into |
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| 13:27 | synaptic space. And the clearance of , there is transport back of |
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| 13:34 | So there's recycling just like the glutamate into the pre and not the terminal |
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| 13:39 | reloading with the transporters of this There's also reuptake of Gaba by the |
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| 13:50 | cells. So when we talk about tri partite synapse, we're also talking |
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| 13:55 | glial cells not only for drawing and involved in synaptic transmission and the side |
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| 14:02 | synapses, but also in the inhibitory . So, if there is a |
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| 14:10 | bit more of this gal, but gets released here in the synaptic |
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| 14:14 | it can actually spill over and activate extra synaptic G. So, and |
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| 14:24 | ones that are located in uh within synapse, it's called basic inhibition and |
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| 14:35 | inhibition looks something like on the order the IP SP. So you will |
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| 14:40 | IP SB certain art pattern of IP and that's a basic inhibition. So |
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| 14:47 | kind of a inhibition pattern and versus tonic inhibition which is recorded outside of |
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| 14:55 | synopsis that once there is Gaba release spillover, it's sort of a has |
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| 15:03 | tonic continuous de uh hyper polarization. . So just hyper polarizes and stays |
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| 15:13 | until it gets unbound, it gets . But it's, it's prolonged this |
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| 15:19 | kind of activation of the hyper The one more important point on this |
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| 15:28 | is KCC, which stands for K C chloride co now C co |
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| 15:40 | So there are KCC, in this , KCC, two transporters that will |
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| 15:49 | transporting potassium and chloride to the outside the belt. And we'll, we'll |
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| 15:57 | back to this because why it's important because once you activate gab a |
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| 16:04 | it's going to conduct fluoride. So an abundance of chloride and there are |
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| 16:12 | that keep chloride on the outside of cell. But also in this |
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| 16:15 | it uses potassium or cot transport and synoptic when you look at the Gaba |
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| 16:25 | . And in this case, it's a receptor, it's ionotropic that has |
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| 16:30 | central channel four. It's constructed out five sub units. 123452 of those |
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| 16:40 | alpha one. In this case, of these are better 31 is gamma |
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| 16:46 | , but there are actually different variations the subtypes of the receptors. So |
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| 16:52 | almost like a little play mosaic that can have uh two alpha receptors or |
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| 17:00 | beta receptors. One alpha uh two , it switches around and that's what |
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| 17:07 | the functionality of different gamma A receptor . And of course, the two |
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| 17:14 | that are shown here, I'm gonna at them uh a little bit greater |
|
| 17:19 | throughout this lecture is the two sides Gaba will be binding. So be |
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| 17:25 | where Gaba binding site is indicated. . OK. Which one? That's |
|
| 17:36 | ? Yeah, tonic inhibition. And to a certain degree, it's a |
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| 17:41 | of normal, but it can be abnormal too. So it is associated |
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| 17:47 | a pathology and it's typically associated with loss of tonic and that loss of |
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| 17:55 | inhibition has been implicated in seizures and . So it's unusual that we have |
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| 18:01 | that there is an abnormal increase in inhibition but typically loss or maybe we |
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| 18:06 | in these early stages. We're just more of a loss of function as |
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| 18:11 | relates to tonic inhibition can contribute to excitability and, and and seizure |
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| 18:21 | And also the loss of phasic would equally so even stronger. OK. |
|
| 18:28 | let's let's talk about this. We looked at the glutamate cycle and we |
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| 18:33 | that glutamate gets released. And of , poop glutamate, you talk is |
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| 18:39 | to target and MB A kyrus and Cyprus poop on the nole cells. |
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| 18:49 | , glutamate year is pictured as we understand that there are glutamate transporters and |
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| 18:58 | glutamate transporters are located on neurons. in this case, GLT one, |
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| 19:05 | is gluten, they transported GLT one for yourself. And so it's gonna |
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| 19:11 | it back in to the prey optic . It's gonna reload the bicycle. |
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| 19:16 | it's gonna release nearby Leo who used transport as GLT one and glass. |
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| 19:27 | two glial gluten they transport as a site. Don't worry about all. |
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| 19:34 | not a biochemist. So I'm not ask you questions about the TC A |
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| 19:38 | , Susanna alpha Keto glu Tora. a lot of details in here, |
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| 19:44 | not gonna ask questions about it, honestly, I dug for this |
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| 19:48 | for like an hour trying to isn't there a good diagram that shows |
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| 19:53 | whole cycle between glutamate and Gaba and ? And so that's what I thought |
|
| 20:01 | was the best actually. Uh but key points that I'm trying to make |
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| 20:06 | glutamate gets released it's transported back into . It also gets transported into Glia |
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| 20:13 | Glia, glutamate gets converted into glutamine then it gets release extra cellular. |
|
| 20:24 | we will say like what's going on is there vesicles? So like, |
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| 20:28 | when we don't know, we'll just there's special shuttles for things, shuttles |
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| 20:32 | ammonia, the shuttles for glutamine, just shuttle we just when we don't |
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| 20:37 | really handling but shuttling is a good to think about. I want my |
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| 20:43 | recovered. Oh no, go So this glutamine also from GLU uh |
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| 20:53 | re uptake by another transporter glutamate transporter and gets entered into a cycle where |
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| 21:03 | gets converted into glutamate by side of and can get leased. This is |
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| 21:11 | we talked about already in the But this is just the reiteration of |
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| 21:15 | tripartite and the glutamate cycling. So say, OK, and then we |
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| 21:21 | of in my previous class, we mentioned it very briefly and we never |
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| 21:24 | about Gaba. We almost say that is a transporter for Gaba, |
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| 21:31 | But then it's kind of a we the the whole idea. OK. |
|
| 21:35 | happens to it? So what happens it is that when Gaba gets released |
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| 21:43 | the inhibitory synapses for moving down to this side, this is Gabba, |
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| 21:49 | also has its own presynaptic transporters one with Gabba transporter that will reuptake |
|
| 21:57 | . OK. This Gaba will re it into Vesico as Gaba and releases |
|
| 22:05 | re update it. Vasos releases Now, uh glial cells are also |
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| 22:15 | take up this G Gaba, it its own gaps, transporters. So |
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| 22:21 | are glial Gaba transporters basically, once takes up gamma, it actually |
|
| 22:31 | well, we can go through the thing, Gaba, TSC, the |
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| 22:34 | , you know, movement, it Gaba into glutamate, astrocytes and glutamate |
|
| 22:46 | glutamine, synthese into glutamine. And then spits out this glutamine and |
|
| 22:55 | already look at what glutamate cells do glutamine, they convert it into |
|
| 23:01 | So what do these cells do with ? These cells pick up glutamine through |
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| 23:09 | a different snap transporter. In this , on the inhibitory cells, they |
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| 23:14 | glutamine, they enter into the turn it into glutamate, convert it |
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| 23:22 | the G A. Remember all inhibitory will be G A positive. This |
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| 23:28 | uh uh uh uh uh botanic acid and it converts glutamate into gaba loads |
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| 23:40 | into the vesicles and releases. But so if you stain for |
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| 23:52 | it's not a very good distinguishing factor excited and inhibitory cells. But if |
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| 23:57 | stain for gad, exotic cells do have gad, they have the glutamate |
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| 24:06 | . They don't have the uh gluten decarboxylase. And so now you're seeing |
|
| 24:14 | aside basically can take glutamate and convert into glutamine with this glutamine s so |
|
| 24:24 | can take gaba and convert it into through the TC A cycle and then |
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| 24:32 | into glutamine. And that the gab cells have the ability to import that |
|
| 24:41 | , convert it into glutamate and then Gaba and release Gaba pretty cool. |
|
| 24:50 | that's something that uh usually takes about years of neuroscience to, to |
|
| 24:59 | But we did it in 20 minutes 15 minutes. He likes it. |
|
| 25:11 | . So we spoke so far about we have these IP SPS, but |
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| 25:17 | really didn't start talking about the po channels yet. So everything we've discussed |
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| 25:23 | far was Gaba cells, Gaba release of Gaba, different subtypes of |
|
| 25:31 | Now, we're gonna talk about what . Plus synoptic, what are some |
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| 25:36 | the agents that are involved in the and what are some of the things |
|
| 25:41 | are important for us to understand? . So let's go to this right |
|
| 25:48 | . We'll talk about the fact that like we had ionotropic and metabotropic glutamate |
|
| 25:53 | , we have ionotropic Gaba and metabotropic , ionotropic Gaba is Gaba A. |
|
| 26:00 | Gaba binds to ionotropic, you have receptor. So you have the pieces |
|
| 26:06 | their brain. And this is Gaba , this is the receptor. When |
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| 26:14 | molecule mines to gather a receptor, comes in as chloride comes in, |
|
| 26:25 | causes IP SP and this IP SP typically short and it's referred to as |
|
| 26:35 | A IP SP. And that means the number and potential from about minus |
|
| 26:41 | millivolts is gonna get hyper polarized around 65 millivolts. And that is if |
|
| 26:49 | have multiple synapses act that the same measures for EP SPS that we talked |
|
| 26:56 | also apply for IP SPS. An of single synapse release of vesicle with |
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| 27:03 | will result in a fraction of a of old hyper polarization in this |
|
| 27:10 | OK. So you can have really small EP SPS. If two vesicles |
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| 27:17 | activated or two synopsis is gonna be the size, triple the size so |
|
| 27:23 | and so forth, it can grow size. So, chloride conductance inside |
|
| 27:28 | cell will cause this inhibitory hyper polarization . And we'll come back to |
|
| 27:36 | This is gonna be our gala be and we'll see is linked to G |
|
| 27:46 | complex. So Gaba a activation will influx of fluoride will cause hyper |
|
| 27:58 | And this is most of the synaptic in the cns glycine mediates non Gaba |
|
| 28:06 | applic inhibition. So when we talked glycine as a cofactor, glycine is |
|
| 28:12 | signaling molecule in the spinal cord and very abundant in the spinal cord. |
|
| 28:18 | cells in the spinal cord inhibitory cells use both Gaba and Glycine in the |
|
| 28:24 | MS Gaba is the most dominant, there's still uh lysergic inhibition. Don't |
|
| 28:31 | that Gaba receptor is also a site all of these different chemicals have combined |
|
| 28:37 | it. So the most common one a lot of people consume is alcohol |
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| 28:42 | ethanol. The other ones such as or barbiturates. Benzodiazepines or barbiturates, |
|
| 28:51 | gonna come back and talk to uh them at length. When we talk |
|
| 28:55 | epilepsy and therapies, what we call convulsant drugs, sometimes anti epileptic |
|
| 29:03 | but really the anti convulsant drugs. a lot of control uh hyperexcitability of |
|
| 29:11 | balance of excitation of inhibition. So have this scale the balance of excite |
|
| 29:18 | excitation and inhibition. If, if have too much excitation, if the |
|
| 29:25 | increases, this balance is gonna get . And so a lot of therapeutic |
|
| 29:32 | would be to increase the inhibition because you increase the inhibition, you can |
|
| 29:39 | this excited or inhibitory metal. So lot of strategies and neurological disease in |
|
| 29:47 | , that wants to control is boosting . And that essentially suppresses neuronal |
|
| 29:56 | suppresses neural networks causes these IP SPS B as it's illustrated here, Gaba |
|
| 30:07 | is a metabotropic G protein coupled receptor activation of this metabotropic Gaba receptor by |
|
| 30:17 | . What it does is there's no here. It can actually cause a |
|
| 30:25 | in the membrane potential. So that's we didn't talk about. And glutamate |
|
| 30:30 | metal glutamate receptors don't really contribute much change in numbering potential. The ga |
|
| 30:36 | beard actually do contribute indirectly and they so by opening nearby potassium channels, |
|
| 30:46 | leaving positive charge leaving is gonna make inside of the membrane more negative or |
|
| 30:53 | in this case closing calcium channels. you'll see that this is most of |
|
| 30:59 | presynaptic of regulating neurotransmitter release or activating cascades such as a dental cycle, |
|
| 31:09 | MP protein kinase A which can positively an MD A receptor and cause an |
|
| 31:17 | of calcium. And that we talked an MD A receptor is uh capable |
|
| 31:21 | conducting. So it's a very different , but this activation of Gaba B |
|
| 31:31 | will actually cause a slower and typically hyper polarization in the network. And |
|
| 31:41 | this is Gaba VIP sp when, , when uh Gaba gets released and |
|
| 31:49 | binds to either the G protein coupled or the channel channel gets activated immediately |
|
| 31:57 | immediately. And that's why you have early G DS P right here. |
|
| 32:04 | this activation of a nearby channel, example, potassium channel here and potassium |
|
| 32:12 | charge leaving and causing the hyper Here. This comes with some |
|
| 32:18 | this delay right here because you have activate the G protein. The G |
|
| 32:22 | has to slide over the catalytic of onto the nearby piece of membrane where |
|
| 32:27 | have this channel has to open the . In this case, potassium |
|
| 32:34 | So therefore, this Gaba B right comes with a comes with a |
|
| 32:41 | but you have 22 hyper polarization. you have a shorter one, a |
|
| 32:47 | inhibition through Gabba A and a delayed that is slower but longer lasting through |
|
| 32:56 | V receptor activation. That's po synaptic the potassium channels. Gabba A and |
|
| 33:05 | B will have their own respective agonists antagonists. And we will actually talk |
|
| 33:10 | bicuculline in the next slide which is Gabba A receptor antagonist. So this |
|
| 33:17 | a pretty typical response that one would . And in this case, these |
|
| 33:24 | were done in the developing visual system a pretty typical response that one would |
|
| 33:30 | following a a stimulus is that there be an EPSB because nearby on this |
|
| 33:39 | on this membrane, there are OK? And there's going to be |
|
| 33:47 | here, there's glutamate receptors. So have EPSP glutamate will bind here and |
|
| 33:58 | nearby synopsis will activate Gaba that will followed by Gaba A IP SP that |
|
| 34:06 | followed by Gaba B IP SP. that's exactly what's depicted here. So |
|
| 34:12 | have this steep EPSP here that's followed the early inhibition from the Gaba A |
|
| 34:17 | late inhibition from Gaba B. And if you activate it, you see |
|
| 34:26 | followed by IP sp, followed by sp. You can overcome, you |
|
| 34:32 | overcome this inhibition by producing stronger and stimuli, cedary stimuli. So what |
|
| 34:40 | mean is when excitation inhibition is there's certain control of excitation by |
|
| 34:47 | If you block inhibition of bicuculline, is the trace where you have ETS |
|
| 34:53 | followed by a TSP. But in presence of bicuculline, which is |
|
| 34:58 | a antagonist, this excitation becomes And now you have this prolonged and |
|
| 35:05 | depolarization that we referred to as plateau . So this is the plateau potential |
|
| 35:13 | during plateau potential, it's not only sodium influx, it's also the calcium |
|
| 35:18 | and the calcium influx that happens. what does it tell you? Tells |
|
| 35:24 | that Gaba a start over the break you have a normal circuit with excitation |
|
| 35:32 | inhibition, excitatory and inhibitory synopsis nearby there's going to be excitation followed by |
|
| 35:41 | . If you increase the stimulus, gonna see more excitation, increase the |
|
| 35:45 | , more, you'll see more It's going to correspond to some sort |
|
| 35:50 | a code, the strength of the versus the amplitude and the duration of |
|
| 35:55 | response. But if you block Gaba inhibition, if there is no hyper |
|
| 36:03 | coming from Gaba A, all of sudden, you lost the control over |
|
| 36:08 | synapse and excitation takes over. So is the main focus. The hydroxy |
|
| 36:17 | cloth then is also the kind of similar to uh flo. So it's |
|
| 36:25 | an antagonist, but in this it's an antagonist for Gaba beer receptor |
|
| 36:32 | Gaba V receptor. If you block V receptor, when it does, |
|
| 36:36 | prolongs this inhibition because Gaba A is . So you will have EP SPS |
|
| 36:43 | you'll have to evoke really strong stimulus order to overcome the Gaba A IP |
|
| 36:53 | . But if you block this Gaba , the only thing that it |
|
| 36:57 | if you block Gaba B is basically it this excitation a little bit |
|
| 37:05 | It doesn't have a profound effect. A is the initial strong and fast |
|
| 37:14 | , right? Gaba B, if B is blocked, it's just going |
|
| 37:18 | prolong this excitation, you'll still have break following it. So it will |
|
| 37:26 | . This is called synaptic activity, or shaping because what we're doing is |
|
| 37:33 | with excitation patterns and these diverse inhibitory , we're sculpting these traces, whether |
|
| 37:40 | going to be excitatory or inhibitory. . Now it's uh gabba synapse and |
|
| 37:49 | synapse. Gabbana releasing Gaba Gaba receptors fluoride responsible for early I BS B |
|
| 38:00 | V activation will open the potassium photic. It will contribute to Gaba |
|
| 38:06 | changing the membrane potential of the I B gab receptors. And if you |
|
| 38:12 | look up, this is an older . But if you still look |
|
| 38:16 | this is from 2012, I found from last year. It still is |
|
| 38:20 | the same way of representing it and using bi Orender instead of hand drawn |
|
| 38:26 | like it was 10 years ago. But yeah, GB receptor and the |
|
| 38:33 | and that's where they interact with voltage calcium channels. Remember, voltage gated |
|
| 38:38 | channels are necessary for neurotransmitter release. what they do is they block voltage |
|
| 38:43 | calcium channels. Therefore, they block of G OK. So they can |
|
| 38:48 | the south plus synoptic. They can inhibit its own release of Gaba and |
|
| 38:55 | are referred to as gamma B auto . So, auto receptors, Gaba |
|
| 39:00 | on the cells that release Gaba, there are also hetero receptors. These |
|
| 39:07 | Gava v hetero receptors and the nearby synopsis. So if there is a |
|
| 39:13 | of this Gaba and it spills it can actually activate presynaptic Gava V |
|
| 39:21 | . Stop the influx of calcium and the release of glutamate. Mm |
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| 39:29 | when the exci synopsis activate an MD receptor, there's an influx of calcium |
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| 39:36 | it turns out that calcium influx in the cells and interacting with Cal and |
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| 39:43 | can interact with Gava view receptors which going to hyperpolarize these cells o synoptic |
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| 39:52 | because they hyperpolarize these cells, they're to block an MD A receptor |
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| 39:58 | Remember that an MD A receptor is to be open if you have glutamate |
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| 40:02 | if you have depolarization, but by, by essentially blocking the, |
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| 40:11 | hyper polarizing through potassium channels, it's . Now, the activation of an |
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| 40:17 | A receptors, it's not allowing for postsynaptic cell to hyperpolarize. And in |
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| 40:25 | , there are also Gaba V receptors are shown here on the postsynaptic |
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| 40:32 | Uh This is uh very similar to we're seeing here. So this would |
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| 40:39 | an inhibitor synapse. This would be excitatory synapse and you can see how |
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| 40:44 | all intertwined together. And after you see how it's all intertwined through |
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| 40:49 | synthesis too and the interactions with So what do neurons do? They |
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| 41:00 | hundreds thousands and sometimes hundreds of thousands excitatory inputs and inhibitory inputs. Remember |
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| 41:08 | a single neuron here that is shown in green are all gluon receptor |
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| 41:14 | That means that a very light excitatory , excitatory response. These are GIC |
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| 41:19 | inhibitory response. So all of these , excitation IP S PE PSP followed |
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| 41:27 | PSP. It will be happening regionally . The SOMA needs to integrate all |
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| 41:32 | that information to compute it and to who's winning is there's enough excitation that |
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| 41:40 | be polarized to produce an action potential is inhibition winning and it's balancing my |
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| 41:47 | and sculpting my activity as the output to the other networks. So it's |
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| 41:53 | fast. This neural computation is very across thousands of synapses. How do |
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| 42:00 | view this uh excitatory inhibitory uh network in general is the I balance. |
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| 42:11 | how do we view it sort of a more general network level? So |
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| 42:16 | have excitation, we have a, have a scale and you have excitatory |
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| 42:26 | that is strong. And uh in situation, when the excitatory input is |
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| 42:36 | inhibitory input. So you can see there's an exci input, very small |
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| 42:41 | input. You're like, what do mean by that? Well, because |
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| 42:45 | larger here. Really? So just have to look at these traces |
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| 42:50 | enough, you'll see it. So dominates and this neuron is receiving or |
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| 42:59 | uh network is receiving an excited, dominant input. OK. And now |
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| 43:06 | the mean is shifted to excitation that is excitatory. And this is also |
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| 43:12 | be very excitatory, very excited, gonna fire a lot of action |
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| 43:17 | So excitation is winning. Citation is . We balance the network where the |
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| 43:23 | is receiving that equal excitatory input, inhibitory input here where the net input |
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| 43:32 | around zero around noise level because it's zero the difference between the two, |
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| 43:37 | it's indistinguishable from the noise, you have very sparse spiking very sparse |
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| 43:45 | That's a typical condition. Actually, balanced network, these neurons unless they're |
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| 43:51 | really strong in unless there is like synchronized engagement to perform a task. |
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| 43:57 | neurons sitting in the brain, they'll receiving excited during people through. But |
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| 44:01 | processing going on all the time. their spiking is gonna be very |
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| 44:07 | Now, what happens if you increase ? In this case, the inhibition |
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| 44:12 | dominant and has shifted the net So with inhibition now inhibited the stent |
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| 44:20 | you inhibited the cell. So they produce a spike and sometimes not at |
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| 44:29 | . And so the brain operates in dynamic ranges. It operates from the |
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| 44:36 | shifting toward excitation and glutamate being dominant transiently as soon as that becomes |
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| 44:46 | Ep SPS, Gaba kicks in Gabo in and uh remember that glutamine and |
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| 45:03 | release results in more glutamine, which in more luminate but also more |
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| 45:17 | OK. So we have this ability shift the network dominance or excitation, |
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| 45:31 | by inhibition to balance it out, by inhibition, followed by excitation, |
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| 45:39 | it out and engaging excitation more when really strong stimulus. And so you |
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| 45:48 | now if there's something is wrong with cycling of glutamate or something is wrong |
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| 45:53 | the cycle of Gaba, this balance get impaired and if it gets impaired |
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| 46:00 | , so it's no longer transient excitation in addition, but it's all shifted |
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| 46:06 | excitation. Now, the brain tissue hyper excitable. It's potentially having too |
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| 46:13 | activity and it's potentially hyper excitable Ok. So we talk about Gaba |
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| 46:21 | the time as inhibitory neurotransmitter. I'm tell you a story that it's not |
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| 46:28 | the case that Gaba during early development actually s and in very simple |
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| 46:38 | that's because during early development, there's lot of chloride inside the cells. |
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| 46:44 | when Gaba activates Gaba receptors, the fluxes out of the cell. But |
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| 46:52 | negative charge leaves the cell, what to the inside of the cell, |
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| 46:56 | becomes more positive. So that means during early development, Gaba is actually |
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| 47:05 | because there is a different concentration gradient fluoride that gradient changes as synopsis neurons |
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| 47:13 | brains mature over time. And at point, fluoride is low in the |
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| 47:23 | and activation of Gaba receptor by Gava cause influx of fluoride negative charge coming |
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| 47:30 | the cell. It's going to hyperpolarize nerves. And what it shows it |
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| 47:39 | you that there is this NKCC which again, we're talking about this potassium |
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| 47:48 | co transporter. In this case, we looked at KCC, this is |
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| 47:56 | . So it's sodium potassium co In this case is bringing sodium and |
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| 48:03 | on the inside, but also bringing . And there's a lot of that |
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| 48:09 | in the early development. Therefore, loading up the south with chloride. |
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| 48:16 | then there is a reduced amount of expression of NKCC as neurons mature. |
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| 48:23 | therefore the chloride gradient changes, there's chloride on the inside of the |
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| 48:29 | And chloride again becomes hyper polarizing by and inside the cells. How does |
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| 48:37 | happen? Let's review some of the that we already know there is an |
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| 48:45 | distribution of these ions across plasma membrane ion scandals cross the plasma membrane. |
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| 48:51 | need channels. When we talk about potential, we we talk about voltage |
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| 48:57 | sodium and potassium channels, you know each one of these ions. So |
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| 49:03 | have a lot of potassium on the and we have a lot of sodium |
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| 49:10 | and chloride on the outside of the compared to the inside of the |
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| 49:15 | So we call unequal distribution on And so what it is is that |
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| 49:22 | normal. Um No, I think same I didn't. That's what I |
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| 49:44 | hoping for is I was hoping to on this, but I don't think |
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| 49:50 | be able to erase it. All has to do with the concentrations |
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| 49:59 | these ions and concentrations of these Using Ner equation allows us to calculate |
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| 50:12 | potential for each item. The nurse using the 21303 RT CF log of |
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| 50:31 | outside versus I don't know on inside , right? Where R is the |
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| 50:40 | constant T is the temperature, Z the valence and F is the fay |
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| 50:46 | , electrical constant. And so we calculate equilibrium potentials for each ion. |
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| 50:55 | call that if you have a channel you have a lot of uh positive |
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| 51:02 | also on one side and little ions the other side. OK. They're |
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| 51:10 | to flug down its concentration gradient. this is the chemical gradient that's going |
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| 51:15 | drive the ions and other side. , as more positive ion enters on |
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| 51:21 | side, it encounters an electrical repulsion which is electrical gradient, so to |
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| 51:29 | . And the value for equilibrium potential this millivolt value, for example, |
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| 51:35 | potassium of minus 80 millivolts, that that minus 80 millivolts, potassium force |
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| 51:46 | inside to the outside of chemical there's more potassium on the inside driving |
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| 51:55 | outside. But at this potential of 80 the two forces are equal and |
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| 52:01 | to each other in size. And what the potential is. So now |
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| 52:09 | also can overlap our action potential here when you initiate action potential, once |
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| 52:18 | reach the threshold, you open volt sodium channels or sodium, more |
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| 52:23 | more sodium, more channels and the potential overall, this VM is being |
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| 52:28 | to the ilri potential of the And then it never reaches equilibrium potential |
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| 52:34 | sodium channels close very quickly and then potassium channel is over and then there's |
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| 52:40 | lot of potassium influx of potassium is the membrane potential to its own equilibrium |
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| 52:47 | . Potassium it gets restored with the P A system and it fluctuates from |
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| 52:54 | own. So OK. So everybody that. So let's look at a |
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| 53:02 | here and you can uh wait but can uh should have a race this |
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| 53:09 | I'm probably gonna talk about it. happens if you change the concentration of |
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| 53:23 | ? And in this case, we're about chloride, what happens if you |
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| 53:30 | concentration for chloride? There's two Let's make it simple. This is |
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| 53:39 | number and potential. Let's make a number and potential of minus 60 |
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| 53:47 | It's fluctuating, let's make a equilibrium for chloride minus 65 millivolts. That's |
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| 54:01 | potential. So if Gaba gets if Gaba gets released here, |
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| 54:10 | it's going to to draw the membrane , it's gonna open fluoride channels is |
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| 54:17 | to hyperpolarize it. That's fluoride going . What happens if you shift the |
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| 54:30 | potential? Because you change the ionic and you shift E chloride into a |
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| 54:46 | 55 millivolt reversal potential. Now, Gaba is released, it's actually going |
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| 54:58 | depolarize plasma number. So this is Gaba. This is the right |
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| 55:16 | This is the hyper polarizing Gava. , it's excited for. Yeah, |
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| 55:30 | inhibitory. So during early development, happens in early development, you have |
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| 55:41 | transformer and it's dominating it's over expressed cord inside. Therefore, it's changing |
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| 55:50 | ratio that later you saw on the , it's changing the ratio. And |
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| 55:56 | can do the calculation by plugging in values in the ERNST equation that changes |
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| 56:02 | ratio or changes the concentrations in this of fluoride, more of the chloride |
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| 56:08 | the inside versus outside. Therefore, changes the equilibrium potential value and it |
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| 56:16 | be depolarizing during early development. And the transporters are no longer expressed to |
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| 56:24 | same degree and chloride gradient is now chloride on the outside. Now we |
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| 56:31 | the situation where it's inhibitor and that's mature or adult brands. Now why |
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| 56:41 | is important? Because I think that mechanism, not me, we think |
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| 56:47 | this mechanism which basically makes ya ex to is also a part of neurodegenerative |
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| 56:57 | if Gaba loses its ability to be during, by disregulation of concentration gradients |
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| 57:06 | they happened due to the impaired And so that is the case that |
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| 57:12 | we talk about epilepsy, we will about glutamate transporters in glia and how |
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| 57:18 | contribute to epilepsy, pathology. And be one of the cellular mechanisms that |
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| 57:25 | to seizures. In epilepsy, we talk about chloride nak cot transporter and |
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| 57:34 | Gaba in the early development brain. if that happens in a dull brain |
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| 57:42 | a consequence of a mutation, let's in the MKCC transporter just over |
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| 57:50 | over worked all the time, it now send the brain back into this |
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| 57:56 | early state where Gaba is excited And that becomes a, a |
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| 58:01 | right? If you're using a drug a gamma agonist, you have to |
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| 58:08 | careful, you have to take into what's going on, not only with |
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| 58:12 | receptors, but potentially what's going on the regulation, the homeostasis and regulation |
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| 58:20 | ions inside and outside of the Because that can influence you can give |
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| 58:26 | a gala uh anti epileptic drug. if they have this, this regulation |
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| 58:33 | the transporter and they have a lot chlorine on the inside, it may |
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| 58:39 | it worse because you may cause more by having a Gaba agonist because it's |
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| 58:46 | Gaba agonist to a receptor. And that receptor channel is open and there's |
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| 58:52 | much of Florida on the inside, actually now an agonist for Gabba, |
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| 58:58 | instead of raising inhibition, it actually a citation. So that's another important |
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| 59:03 | to keep in mind when we talk the balancing act between excitation and inhibition |
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| 59:08 | step. And this is sort of introduction. We'll talk exhaustively about how |
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| 59:14 | comes about in epilepsy and seizures uh in the course. So when we |
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| 59:19 | back on Wednesday, I'm actually gonna attendance. It's gonna be pretty |
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| 59:24 | Thursday. Sorry. Uh And uh gonna have uh electron on our modulatory |
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| 59:35 | and move into imaging of the So if we finish it all, |
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| 59:40 | you have your exam um Thursday next . So we have two more meetings |
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| 59:47 | Thursday, this Tuesday. That's why want everybody to be present and then |
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| 59:51 | want everybody to be present for the where we're gonna sign the groups and |
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| 59:57 | . So that's maybe like already like attendances and then I'll take another attendance |
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| 60:02 | by you turning in your project and name on it. So, uh |
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| 60:08 | I appreciate everybody being here. So believe me, I wanted to cancel |
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| 60:11 | lecture today at the weather at the . I was like, hm, |
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| 60:19 | it's all good and the summertime is still to come. Uh any questions |
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| 60:25 | what we've covered? Yeah. OK. That's a great question. |
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| 60:39 | . Um I would ask the same and I don't uh we don't talk |
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| 60:45 | that typically. Yeah, it's, not because glutamate signaling depends on sodium |
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| 60:59 | potassium. It would be much more um to, and it's an influx |
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| 61:10 | of sodium. Um You would have have deprivation of sodium on the outside |
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| 61:20 | the cells. So, it's a good question when we talk about |
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| 61:28 | that's not a common thing that you across and talk about inhibitory glit. |
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| 61:34 | But it's more likely to talk about inhibit uh excitatory gaba. Good |
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| 61:43 | All right. See you on |
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