| 00:01 | This is Lecture five of cellular And what we ended up discussing last |
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| 00:09 | was essentially the non culture for glutamate channels. So these are ligand gated |
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| 00:18 | . We talked about different components. I have pointed out to the class |
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| 00:24 | lecture materials for you to read a bit more, but I would like |
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| 00:29 | you to know the structure of these have one through them. Before that |
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| 00:35 | is a flip flop domain that there a clamp shell clam shell like structure |
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| 00:42 | the agonists would be trapped in which this binding changes the conformational structure of |
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| 00:49 | channel allows for the flux of the . And we talked about agonists |
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| 00:57 | We also talked about competitive antagonists. if you recall competitive antagonists are going |
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| 01:04 | compete for the same side that agonists trying to activate or open the |
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| 01:10 | The competitive antagonists will try to compete the same side. So there's this |
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| 01:15 | of binding affinity and what that means the higher the binding affinity for a |
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| 01:21 | molecule. So receptor may have very binding affinity for an agonist and that |
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| 01:28 | the low concentration of that agonist is bind to the channel and activate the |
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| 01:34 | and it may have a low affinity antagonist. Low affinity means you have |
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| 01:39 | have a lot of that antagonist in for for for it to compete with |
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| 01:44 | agonist. So this is basically competitive and they're also alle ist eric modulators |
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| 01:54 | we talked about. So they are and antagonists. If we think about |
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| 01:59 | . Opening the channel antagonist closing the then or competitive antagonist closing the channel |
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| 02:06 | the same side of agonists. And Terek modulators are distinct sites on this |
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| 02:16 | . So unique size and their modulators they don't quite open the channel, |
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| 02:23 | quite close the channel but they regulate opening and closing of the channel. |
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| 02:27 | may influence for it to open more stay open longer. Uh and they |
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| 02:33 | their own side. So they could negative Alistair IQ modulators but they can |
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| 02:39 | positive Alistair IQ modulators and negative is that's something that's going to interfere with |
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| 02:46 | function of an agonist and a positive IQ modulator and agonist combined to one |
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| 02:52 | of the channel positive Alistair IQ modulator on a different side of this channel |
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| 02:58 | both of them are doing the same . So it's supporting role for activation |
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| 03:05 | example with a positive Alistair IQ modulator an agonist. Mhm. Uh So |
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| 03:14 | then talked about reactive leo sis and happens in the case of inflammation and |
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| 03:23 | and we discussed the up regulation of tropic glutamate receptors. So then we |
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| 03:29 | we are going to talk a little about meta protropin glutamate receptors. What |
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| 03:33 | they have. But this was an how uh glutamate signaling and astrocytes and |
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| 03:42 | on the medical tropical ultimate receptors. astrocytes will influence the amount of glutamate |
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| 03:48 | is responsible for excitation and that is to neurons and that is going to |
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| 03:55 | to these glutamate receptor channels that we're about. So these are a nina |
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| 04:02 | channels and point an M. A. We already discussed a little |
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| 04:06 | about that but essentially we talked about A responsible for the early initial component |
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| 04:13 | the E. P. S. . Which is excited to be part |
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| 04:16 | potentials. And an M. A. Is responsible for the late |
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| 04:19 | component of E. P. P. Mhm. Um Now how |
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| 04:28 | we record activity in the form of . P. S. B. |
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| 04:33 | do we record activity in the form action potentials? This is typically electro |
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| 04:41 | techniques that we use. So we neurophysiology, electrophysiology, interchangeable electrophysiology is |
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| 04:48 | you can do electrophysiology and um muscle . So then it's not neurophysiology, |
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| 04:55 | electrophysiology on the muscle. The neurophysiology looking at the activity, the pre |
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| 05:02 | cell which is producing the action potential the post synaptic response. And in |
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| 05:07 | case when we were talking about glutamate talking about excitatory post synaptic potential and |
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| 05:12 | response. We're gonna talk about Gaba we'll start talking about gaba maybe we'll |
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| 05:16 | get through Gaba. We're gonna be about the inhibitory response. Excitatory responsible |
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| 05:22 | cell. That means this potential from 65 becomes more positive and it's closer |
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| 05:27 | the south of producer action potential inhibitory synaptic potentials will actually hyper polarized itself |
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| 05:35 | away from the actual potential. So the neurotransmitter gets released here at the |
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| 05:42 | oil terminal and it binds glutamate, post synaptic lee to the receptors. |
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| 05:48 | post synaptic density you'll have collections of kinase receptors posten optically and that glutamate |
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| 05:55 | to AMP and an M. A. Receptors will be responsible for |
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| 06:00 | the excitatory post synaptic potential. So we are recording activity there are some |
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| 06:08 | that are not generating the action So the excited or post synaptic |
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| 06:14 | The graded potentials. E. S. P. S. A |
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| 06:17 | potential action potential is all or That means that if you inject Significant |
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| 06:24 | of current and you're gonna reach the of the threshold for action potential which |
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| 06:29 | -45 million balls. You will generate or non advanced these action potentials. |
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| 06:37 | the way that we interpret cellular responses lot of times is that if the |
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| 06:43 | in here and green is a stimulus whatever you're seeing in the instrumentation whenever |
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| 06:52 | have an electronic switch it's on and . So this is on switch, |
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| 06:58 | current positive current is being injected, cell doesn't respond in this square wave |
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| 07:05 | response. Instead the cell has resisted capacity those properties. And so this |
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| 07:12 | change takes a little bit of You can see it takes a few |
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| 07:16 | it's not immediate on and if the is weak you might get E. |
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| 07:22 | . S. P. S. may get excitation of the membrane but |
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| 07:26 | it doesn't reach the threshold for the potential, the membrane is not going |
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| 07:30 | produce action potentials. Now if the is stronger you will produce action potentials |
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| 07:38 | you reach the threshold value. And the stimulus is stronger the same cell |
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| 07:45 | produce even higher frequency of action So in this case and some very |
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| 07:52 | code neurons encoding the strength of the by frequencies of action potentials. At |
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| 08:02 | point neurons have a limit to how action potentials they can produce in a |
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| 08:07 | amount of time. Or they have boundaries for frequencies how fast they can |
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| 08:13 | . So you can reach that upper limit of pushing the south to fire |
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| 08:19 | frequently as it can. But in the stronger the input, the stronger |
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| 08:25 | stimulus the higher is the number of action potentials and frequency. Because the |
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| 08:32 | doesn't change, action potentials are all on events. So that always the |
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| 08:37 | amplitude. But the frequency it's like morse code and it can go |
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| 08:44 | It can go slower and that means encoding the strength of the stimulus and |
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| 08:49 | information that that neuron will pass on the interconnect itself. So to record |
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| 08:55 | electro physiological equipped activity we typically use clamp recordings and this is a number |
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| 09:06 | examples of patch clamp recordings. So this case we have an electrode that |
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| 09:11 | bring very close to the numbering of cell and we form a very mild |
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| 09:17 | . Physical suction to the membrane and now attached. And so this recording |
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| 09:25 | called cell attached. It's sort of putting your ear to the wall of |
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| 09:32 | room where people are talking. So cell attached mode you're not gonna get |
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| 09:37 | precise information. It's not going to very high applicant information but you're listening |
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| 09:44 | essentially that wall right is like your for what's happening in the room. |
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| 09:52 | in this case for electrode the it's like an antenna. What's happening |
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| 09:57 | the room? Let's sell attachment in cell recordings. You would actually instead |
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| 10:04 | just forming the pressure here and attaching the number rain, you're actually going |
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| 10:10 | rupture the number and you do that with a little bit of mechanical suction |
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| 10:17 | the pipe pad itself and you break member Now, instead of having your |
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| 10:24 | to the wall and hardly discerning the system, what what people are saying |
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| 10:29 | the other side of the wall, you've done here is you made a |
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| 10:33 | in the wall and put your ear is your electrode and now you can |
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| 10:39 | everything that's happening in that room and can hear it quite clearly with good |
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| 10:47 | . Huh? This recording inside out is instead of rupturing the opening like |
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| 10:55 | wholesale recording. Once you're attached to plasma membrane, you kind of shake |
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| 11:02 | electrode physically mechanically. And if you're , these are procedures that you know |
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| 11:08 | skills, years of practice and then hours to do if you shake the |
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| 11:15 | and you you shake a little piece the number and you withdraw it. |
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| 11:21 | now you're like taking a piece of wall and you're gonna study exactly that |
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| 11:27 | of the wall, what what what interested in. So only the channels |
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| 11:31 | are in this piece of the Rain. Only the channels that are |
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| 11:35 | be open and the conductance is in current flexing through this piece of remember |
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| 11:39 | that's what you're going to record. you're no longer recording the whole cell |
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| 11:43 | . You're having an inside out It's literally a patch of a membrane |
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| 11:49 | can be very insightful and very And in fact most of the times |
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| 11:55 | it's a it's a much needed technique out. There's another technique and in |
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| 12:03 | out you actually pull the piece of membrane. But then you apply the |
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| 12:07 | and you break it and if on inside out you just withdrew this membrane |
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| 12:14 | the see the inside of the protein is exposed to your experimental condition here |
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| 12:20 | is the solution and you can put ions or chemicals in the solution right |
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| 12:27 | here instead of the inside. Once membrane RIEN ILs it's the outside of |
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| 12:35 | protein that exposed to your outside environment you say. Well, why do |
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| 12:39 | want to do that? Because there a very interesting studies, especially |
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| 12:46 | you want to have patches on the because you want to isolate certain conductance |
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| 12:51 | like for one channel. So instead recording from the whole cell that will |
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| 12:56 | many different channels, you actually gonna I'm gonna target one part of the |
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| 13:01 | that has a lot of potassium channels I'm going to try to take a |
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| 13:05 | . So my understanding of the system going to be more simple than all |
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| 13:10 | rest of the cell. The other why is some substances do not pass |
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| 13:15 | the membrane. Some substances do not through the membrane and some substances passed |
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| 13:22 | . Remember if they don't pass through membrane then it's really interesting to study |
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| 13:28 | fact that these substances on the outside the protein because they are likely to |
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| 13:33 | found in extra cellular space. If pass through the membrane, you can |
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| 13:39 | expose them to the inside of this , allow for that molecule to bind |
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| 13:45 | then see how it affects the flocks the conductance is through the touch of |
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| 13:49 | membrane that that you're targeting. These the Basically four main techniques attached wholesale |
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| 14:01 | out and outside out techniques. for the outside out when it reveals |
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| 14:08 | exactly are you doing, you're still currents through the ion channels. But |
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| 14:16 | this case you can do chemical and manipulations that target the outside part of |
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| 14:23 | channel without affecting the inside of that molecules that don't pass. And sometimes |
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| 14:29 | don't know where it binds. So want to do inside out and outside |
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| 14:33 | , you see where it has a effect. Sometimes it binds on both |
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| 14:36 | , has two binding sides, but want to see which one is affecting |
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| 14:40 | channel function more. So you could that by isolating inside out. Alright |
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| 14:48 | outside out. No. Now some the recordings are inter cellular and the |
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| 14:56 | that we're talking about here for the cell patch clamp in particular. This |
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| 15:02 | the whole cell patch clamp recording. a couple of things that are happening |
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| 15:08 | that are important to understand When you a large electorate. These electorates are |
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| 15:14 | one micrometer in diameter. For wholesale on the rise, 1-2 micrometer |
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| 15:22 | The cell size is 10 micro There's a diamond over Euro. How |
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| 15:31 | do you think this electrode is not tip of the electrode? What's something |
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| 15:36 | holding in your hand, It's It's humongous. So therefore that electrode |
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| 15:43 | has this huge reservoir of fluid. if you make a hole in the |
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| 15:51 | here, you better make sure that fluid inside the membrane matches the side |
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| 15:56 | plas Mick, fluid apart from your experimental things you want to include, |
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| 16:02 | once you rupture the opening. Let's if you had too much of water |
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| 16:07 | too much ions in the in the pad, then the cell can collapse |
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| 16:13 | cell can uh blow it up and and expand so it can many different |
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| 16:20 | can happen. So what this is , these are called intracellular solutions. |
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| 16:25 | inside there's inter cellular solution inside the and there's the electrode solution. And |
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| 16:36 | electorate solution is you you put as experimenter, you put solution inside the |
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| 16:41 | . It's hollow, it's gloss. you have to make sure it matches |
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| 16:46 | electrode solution. Okay, We can call it internal solution of the electrode |
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| 16:52 | the intracellular solution, intracellular environment of south. Now in wholesale recording you |
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| 17:00 | have low resistance because the diameter of electorate is large. Right low electrode |
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| 17:12 | . But you have high input resistance you actually are tags onto the cell |
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| 17:22 | your input resistance for the electorate becomes input resistance of the cell because you're |
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| 17:27 | everything that's going through that cell. it's high cellular input resistance, it's |
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| 17:36 | better voltage clamp or better space So when you're regulating from this |
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| 17:42 | you have a better ability to command your commanding voltage for the cell, |
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| 17:47 | recording something from the cell, you a better ability to command that |
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| 17:51 | It's called voltage clamp or space It's mostly visualized technique. So it's |
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| 18:00 | that you would approach the cells and the cells in a blind mode without |
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| 18:06 | anything. It happens and it has happen in vivo experimentally quite often. |
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| 18:12 | most of it is visualized under the . Most of these recordings, whole |
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| 18:17 | patch clamps will be done in So in the ditch on the left |
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| 18:25 | and I started talking about the right because it matches the wholesale recordings here |
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| 18:30 | the left, we have intracellular pipettes intracellular recordings. Look at these tiny |
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| 18:38 | wispy diameter, uh maybe 0.1 Micrometer less in diameter. That means whatever |
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| 18:50 | have inside this pie pod, it's gonna very easily leak inside the |
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| 18:57 | So there's virtually no cell dialysis with 0.5 micro meter, even less. |
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| 19:03 | I said, it could be 0.1 meter in the amateur. Just depends |
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| 19:08 | you prepare it in the lab. very high electorate resistance. So when |
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| 19:16 | thinking about resistance, a good analogy think about is water flowing through the |
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| 19:22 | . If you have a lot of and a big hose you're gonna be |
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| 19:28 | to transfer more water. But if have a small hose, you're gonna |
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| 19:33 | to wait. So, and then why is because there's more pressure and |
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| 19:40 | you want to deliver more, you to increase the pressure to push that |
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| 19:44 | through the house. But as far the electrode itself, because it's so |
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| 19:50 | , the electrode itself will have high resistance value. But the cell is |
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| 19:59 | input resistance as you're recording from the , you're really manipulating current, uh |
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| 20:10 | current for voltage manipulations than whole And you cannot really command the sell |
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| 20:15 | well. You cannot tell the seller to command certain voltage potential. But |
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| 20:21 | will see a lot of recordings will in these days will be whole cell |
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| 20:28 | , but you'll still come across some recordings. Now, the advantage why |
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| 20:33 | would want to do these sharp electrode recordings, They're also known as sharp |
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| 20:40 | recordings because the electrode is really, sharp. The tip is very sharp |
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| 20:44 | because you can do it blindly. you don't have to visualize the neuron |
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| 20:51 | a microscope. And you can do lot of this work in vitro. |
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| 20:58 | this is a comparison basically. Most this is in vitro techniques here. |
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| 21:04 | looking at patch clamp recordings, you do them in viva very difficult most |
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| 21:09 | the time you have to visualize. for intracellular recordings, you actually can |
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| 21:15 | them without visualizing them. And you do a lot more work in vivo |
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| 21:20 | these types of recordings. So, in electrophysiology or neurophysiology, most of |
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| 21:29 | recordings in single cells. And we going to be a whole cell voltage |
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| 21:37 | recordings or uh wholesale recordings in So this is whole cell recordings. |
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| 21:46 | are patch membrane recordings for channels. this is stabbing. The electrode inter |
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| 21:54 | early. And because there isn't that dialysis and you're not as concerned with |
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| 22:00 | internal electric solution as much as you when you're ripping a big hole in |
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| 22:05 | membrane and everything that's in this electrode die allies into the cell. So |
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| 22:14 | kind of recordings when you have a of the membrane with channels. These |
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| 22:20 | of recordings allow us to do studies single channels And isolate specific channels. |
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| 22:29 | that patch of the number eight we isolate ample channel or an M. |
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| 22:34 | . A. Channel. We may our agonists and antagonists to block everything |
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| 22:41 | an M. D. A. . So what this illustrates as At |
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| 22:48 | physiological conditions, extra cellular solution contains million dollar magnesium and this is an |
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| 22:57 | . D. A receptor. So goes to how do we take apart |
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| 23:01 | E. P. S. To the early component and late |
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| 23:07 | The way that we do it is have to do these electro physiological |
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| 23:12 | And if we're doing these recordings these single channel recordings. So this is |
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| 23:18 | we isolated an M. D. receptor channel. And what shows you |
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| 23:23 | of the magnesium blog if you release and you have the membrane potential at |
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| 23:31 | 60 million bowls hyper polarized. There's no openings of an M. |
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| 23:36 | A receptor channel in the presence of and that's because if you remember an |
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| 23:42 | . D. A receptor is blocked magnesium here. Okay so there's virtually |
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| 23:48 | opening And you can see that there's opening at -30. There is virtually |
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| 23:56 | car in flowing of zero millet balls the potential. There is a lot |
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| 24:03 | an M. D. A current at the positive potentials. So what |
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| 24:08 | are called these are called voltage clamp . We, as experimenters can tell |
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| 24:16 | the whole cell patch clamp technique that described to you, we can hold |
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| 24:20 | potential at different values. We can that the cell membrane you're going to |
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| 24:25 | at minus 60 minus 30. I'm to apply glutamate and I'm gonna see |
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| 24:30 | there's any fluxus through an M. . A receptor. In this right |
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| 24:37 | you actually take the magnesium away zero , there's no more magnesium and this |
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| 24:44 | shows that a minus 60 mila voles M. D. A receptor is |
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| 24:49 | to be open and active. So proves that magnesium is really blocking an |
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| 24:55 | . D. A receptor because in conditions the left and the right, |
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| 24:59 | have a patch of the membrane, recording an M. D. |
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| 25:02 | Current on the left, you have lot of magnesium and on the right |
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| 25:09 | remove all of the magnesium and you're from the same patch and now you're |
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| 25:14 | the same N. M. A receptor being active in the same |
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| 25:17 | which is in the presence of So this is where we get into |
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| 25:24 | potentials understanding reversal potentials especially the concerns rampant in India receptors. So ionic |
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| 25:40 | flow. Different brain voltages can be as shown in figure a. What |
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| 25:46 | shown in figure eights on the X . You have voltage and mila |
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| 25:52 | Remember that membrane voltage or resting membrane is about minus 65 million volts. |
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| 26:00 | here the voltages on the X axis the y axis you have current by |
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| 26:08 | , current in this direction is outward current on the negative Y axis is |
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| 26:14 | inward current. So this plot or graph is called an I. |
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| 26:23 | Plot. Well I this is the in V. Is the voltage the |
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| 26:31 | value of member and potential at which direction of current flow reverses is called |
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| 26:38 | reversal potential. So you see this here at zero Before zero at negative |
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| 26:48 | -60 -50. This current is inward zero potential. What is the value |
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| 26:57 | the current is zero. But at positive potentials and mill evolves the direction |
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| 27:05 | the current reverses. And that's why point at which the direction of the |
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| 27:11 | reverses is called the reversal potential. this is an illustration of reversal potential |
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| 27:20 | acetylcholine receptor which actually is the same for amp and an M. |
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| 27:26 | A receptors. The value is the . But the plots are not always |
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| 27:32 | same. Remember we talked about how channels when we talked about action potential |
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| 27:41 | that these channels are voltage gated. do we have in an M. |
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| 27:48 | . A receptor? We have a that is gated by both ligand and |
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| 27:58 | ample is gated by Ligon. So binds to Tampa alma channel is open |
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| 28:06 | in order to open an M. . A. S. Gated by |
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| 28:09 | by neurotransmitter glutamate and by voltage. in this case it's not the gate |
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| 28:16 | it's the magnesium block that the voltage alleviate from an M. D. |
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| 28:21 | . Receptor. So if we look that ivy plots for the E. |
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| 28:29 | . S. P. The excitatory synaptic potential. This is the holding |
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| 28:37 | minus 80 million volts minus 40 plus . This is what the experimenter is |
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| 28:43 | using Patch plan physiology and voltage You're dictating this potential This line here |
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| 28:53 | the stimulus which is glutamate following the . Do you have an E. |
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| 29:00 | . S. P. In this your recording currents you're holding voltage |
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| 29:05 | Equals Ir arms law. You're holding your record according current current. I |
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| 29:15 | you have a stimulus and the same slot And you're holding the seller's |
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| 29:23 | I'm gonna hold it is positive 20-40 . And you're gonna ask a |
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| 29:32 | I'm going to measure the amount of at the very peak of this |
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| 29:37 | P. S. P. And going to call this? The peak |
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| 29:41 | or the late early component. Early Or the P. Current here. |
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| 29:48 | after the stimulation, this is 50 timescale, some five milliseconds later. |
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| 29:55 | gonna measure this P component. The component. I'm also after I produced |
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| 30:02 | stimulus here. Different potentials. 2040 . I'm also gonna measure this other |
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| 30:10 | line here. Which is the late or the late current of E. |
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| 30:15 | . S. P. Huh? as a measure the early component, |
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| 30:25 | gonna make it. That you? plot. How does this early P |
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| 30:31 | changes as I change the voltage from 80 minus 40 minus 20 even minus |
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| 30:39 | , 200 minus 150 180 50 and on. And these triangles represent the |
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| 30:51 | component. So these triangles filled and empty triangles is the early component of |
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| 31:02 | . P. S. P. what does that tell you about? |
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| 31:06 | ? Early component of E. S. B. It has a |
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| 31:10 | I. V. Plot, It's like a straight line just like |
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| 31:18 | saw here which is a saddle clothing chairman. What else? It has |
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| 31:27 | reversal potential. zero Miller votes remember is I. D. Plot. |
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| 31:35 | again this is outward current here. current is outward current and PICO amperes |
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| 31:42 | and this is inward current just like is here, negative car and its |
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| 31:47 | current. So the early component of excitatory post synaptic potential is linear And |
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| 31:55 | reverses a zero Mila bells. Alright let's measure the late component. It's |
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| 32:03 | same experiment replied glutamate we stimulated here glutamate. We first measured the early |
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| 32:13 | and we saw that it is linear . V. Plot. We're now |
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| 32:17 | to take and measure the late component the PSP. When we measure the |
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| 32:22 | component of E. P. P. We see that at the |
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| 32:26 | polarized potentials minus 100 minus 80. this is the circle here build circles |
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| 32:38 | is almost around zero PICO amperes And it starts increasing at -60 -50 -40 |
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| 32:50 | . It reaches the maximum current value on the current scale axis And then |
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| 32:57 | reverses a zero merlot vaults and then conducts in a linear fashion. The |
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| 33:05 | current so that inward current has this component and once it reverses it becomes |
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| 33:14 | outward. So both of these early late components which is early Zampa and |
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| 33:23 | card is an M. D. . Both of them are reversed. |
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| 33:28 | . The big difference is ampara is I. D. Plot and |
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| 33:33 | D. A. Is not the why an M. D. |
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| 33:37 | Is not linear is because if these here minus 100 minus 60 magnesium is |
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| 33:45 | the channel and the really strong conductance when there is initial deep polarization through |
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| 33:53 | receptor. And that's when an D. A. Starts acting as |
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| 33:57 | detector alleviates magnesium block block and conducts this plot here. There's two more |
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| 34:10 | . So first of all there is triangles that are filled. It's |
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| 34:14 | it's ampara late circles that are This is an M. D. |
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| 34:20 | . Then we have these open circles in open circles we added a |
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| 34:29 | Which is a specific N. D. A receptor antagonist. We |
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| 34:34 | it earlier when we mentioned that they their specific ampara and M. |
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| 34:39 | A. And key Nate agonists. then in that same graph we mentioned |
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| 34:45 | they have their specific antagonist. So seeing Q. X. And A |
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| 34:50 | . V. Is for an D. A. Receptor is an |
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| 34:56 | . So in the presence of this you now want to repeat the same |
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| 35:02 | . And you see if you apply M. D. A receptor |
|
| 35:06 | And this is your test. Is specific to an M. D. |
|
| 35:09 | . Or is an antagonist going to the early component? So if you |
|
| 35:15 | to check whether this antagonist affects the component, you do the same |
|
| 35:20 | You apply glutamate and you measure the in current five milliseconds following the stimulation |
|
| 35:27 | early components. And you get the linear graph here open triangles and close |
|
| 35:35 | because this is not affecting the early . So this is one part of |
|
| 35:39 | experiment. This A T. Blocker antagonist. It's not affecting ample |
|
| 35:45 | specific to an M. D. . This is what I ordered in |
|
| 35:49 | book. So what would you Now I would expect that if I |
|
| 35:55 | a P. D. And I the late component that it would be |
|
| 35:59 | significantly. And so this blue area the curve is the late component. |
|
| 36:08 | blue area essentially is the contribution of M. D. A receptor. |
|
| 36:14 | you look there's actually more area under curve and blue than it is under |
|
| 36:21 | A. So the conductance overall conductors stronger than an M. D. |
|
| 36:25 | . Receptor. But if you repeat experiment you stimulate and you're gonna measure |
|
| 36:32 | component and you saw that you have closed circles so it's nonlinear late |
|
| 36:38 | But now you applied a PV and gambling that it's going to affect late |
|
| 36:42 | because a P. V. And M. D. A. |
|
| 36:45 | specific blocker. And indeed then you these open circles which is this flat |
|
| 36:53 | lingering around zero. Biology is very to have everything. 0 to have |
|
| 37:00 | 100% blocked. But you can see these open circles are now indicating that |
|
| 37:08 | late component and the presence of a . D. Has been blocked. |
|
| 37:12 | is no more current. And this a number of experiments and techniques that |
|
| 37:18 | into this. So patch clamp isolating channel activity from these patches of the |
|
| 37:27 | , making sure that you are having correct environment and in this case making |
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| 37:33 | that you're applying the toxin and that is binding to a specific part of |
|
| 37:37 | channel so that you can definitively demonstrate experiments. So there are two different |
|
| 37:43 | plots. The early components of P. S. P. |
|
| 37:47 | A linear plot and the late component is longer lasting and maybe even more |
|
| 37:54 | than the transfer of the charge is linear. That's an M. |
|
| 37:59 | A. And then D. A , a very important early development and |
|
| 38:13 | . D. A receptors are present the synopsis before amber receptors are |
|
| 38:21 | But there's synopsis are called silent synopsis in order for this an M. |
|
| 38:28 | . A receptor channel to function you to kick out magnesium to kick out |
|
| 38:38 | you need deep polarization and that depreciation from amper. So in early developmental |
|
| 38:48 | glutamate may be released and is released advanced NMDA receptors. But guess what |
|
| 38:55 | cell members about D. Polarized. amper receptors are not there and then |
|
| 39:01 | . A receptors will not open and synapses will remain silent or unresponsive and |
|
| 39:08 | you have this term of the silent and then the receptors were talking about |
|
| 39:17 | subunits, how you form the sub we discussed the AMP A receptor |
|
| 39:23 | an M. D. A receptor composition may change during the development. |
|
| 39:32 | . R. To a subunit subtype be dominant on M. D. |
|
| 39:36 | receptor and are to be becomes more in the later stages. So the |
|
| 39:43 | of these subunits that code for an . D. A receptor can change |
|
| 39:47 | a part of development as a part the activity dependent processes also. So |
|
| 39:54 | M. D. A receptor is important for learning and memory. And |
|
| 40:00 | be talking about plasticity. And in lectures from now we actually have our |
|
| 40:12 | coming up and almost it's it's actually thursday or is it on Tuesday? |
|
| 40:28 | ? Sorry I forgot what day of week on then, Monday. |
|
| 40:36 | In two weeks. So before that have this lecture we have Wednesday's lecture |
|
| 40:45 | excited or inhibitors circuits. We have following monday's electron elasticity heavy in |
|
| 40:53 | And then we have our review coming . So just to remind ourselves so |
|
| 41:00 | we talk about listed city that's why important for us to understand how an |
|
| 41:05 | . D. A receptor is so for plasticity, why it's perfectly positioned |
|
| 41:14 | pick up the pre synaptic signal and and to also pick up the pot |
|
| 41:19 | deep polarization. So it has these properties of pre synaptic and post synaptic |
|
| 41:25 | combine what's going on pre synaptic What's going on boston optical, there's |
|
| 41:31 | enough deep polarization posson ethically it's not to bind these two interactions. So |
|
| 41:40 | we talk about learning and memory, dendritic spines that we talked about the |
|
| 41:47 | common sides of synopsis of neurons and the most plastic elements. We talked |
|
| 41:54 | fragile like syndrome how you have abnormal who have abnormal processing and connectivity and |
|
| 42:01 | have mental retardation and other issues. these spines they constantly have to change |
|
| 42:09 | structure and they have to change the that they're expressing in the membrane. |
|
| 42:13 | receptor channels. So N. D. A receptors are very important |
|
| 42:21 | the concept of L. T. . Which stands for long term potentially |
|
| 42:27 | or long term plasticity. And we don't worry about it today. Just |
|
| 42:35 | enough long term plasticity. We have lecture and plasticity. We'll talk about |
|
| 42:41 | long term and and and the differences them. Yeah you said early development |
|
| 42:54 | whose only enemy and chance. So where do come from? Is |
|
| 42:59 | a certain point? Yes. Yeah exactly that's a very good |
|
| 43:06 | And it depends on what system it and it depends on the animal. |
|
| 43:13 | If they are late post natal developing you know some certain animals will have |
|
| 43:19 | late developing systems which are interesting to because their post natal and and the |
|
| 43:25 | systems maybe prenatal everything prenatal is so harder to study And especially if you |
|
| 43:32 | experimental manipulations you know. So you're talking about two systems. 2 organisms |
|
| 43:41 | prenatal. So uh so well well there is no kind of a set |
|
| 43:53 | . Oh the first week is an . D. A second week is |
|
| 43:57 | . But these changes are gradual and different systems they're also different times. |
|
| 44:04 | let's say in certain systems it's prenatal other animals and other systems. These |
|
| 44:10 | could be even post natal, the of the sub units of an |
|
| 44:16 | D. A. Receptor which will an M. D. A. |
|
| 44:18 | function and then insertion of ample And a lot of what happens in |
|
| 44:25 | in the developing brains is because of waves which de polarize the cells and |
|
| 44:33 | polarize enough in NBA receptors to activate . But the synopsis of silent the |
|
| 44:40 | transmission part of glutamate is released and D. A. Will stay silent |
|
| 44:45 | But if there's a large calcium Polarization wave due to activity and then |
|
| 44:51 | . A receptors will wake up. there's an alternative mechanism inactivating them. |
|
| 44:56 | it's not through neural transmission. That's they're called silent. So now. |
|
| 45:05 | these receptors change as part of the . Their subunits change. Uh Tampa |
|
| 45:13 | very fast and it can move across membranes and into the synopsis from extra |
|
| 45:20 | spaces into the synaptic spaces in a fast fashion. So the plasticity process |
|
| 45:27 | not only strengthening the synopsis and having receptor channels more open and active but |
|
| 45:34 | potentially inserting new receptor channels from the of the cell bringing new receptor channels |
|
| 45:44 | extra synaptic space is sort of a upon the reserve and that is an |
|
| 45:50 | dependent process everything that's happening in the the refinement we have early on everything |
|
| 46:00 | to everything very non specifically. and have a lot more synapses when we're |
|
| 46:05 | and we end up with when we're and during this process as we're exposed |
|
| 46:11 | different stimuli, sensory intellectual um uh uh sensory touch, all of |
|
| 46:21 | you know not just vision, we refine these connections. And this |
|
| 46:27 | of refinement is the process of And so you have to have an |
|
| 46:32 | . D. A receptor to have . You have to have mobile ample |
|
| 46:38 | to to to support the plasticity. there is more activity, you're gonna |
|
| 46:47 | more receptor channels sometime unless you're giving on that synapse and that synapse is |
|
| 46:53 | unresponsive to stimulus. So this other part of the uh slide actually talks |
|
| 47:05 | ample channel so both of these as can see a very important an important |
|
| 47:10 | D. A. And the major GIC channel subtypes what we said originally |
|
| 47:18 | all in M. D. Receptor channels will allow for the conductance |
|
| 47:21 | calcium and an ample receptors you can certain ample receptor channels that will allow |
|
| 47:30 | to come in and others that will allow calcium to come in. That's |
|
| 47:34 | a question for an M. A receptor. But for ample receptor |
|
| 47:38 | it is. And if you look the sequence and if you if you |
|
| 47:42 | the protein channels to build out of very long polyp peptide uh chains of |
|
| 47:48 | acids and their you know building to tertiary of ordinary structures and there's thousands |
|
| 47:57 | these amino acids that would be coding a small region of that podium. |
|
| 48:03 | if you take one of them from . two region Q. Which is |
|
| 48:10 | and this is glue R. Two . Which is ample receptor that has |
|
| 48:17 | . Which is glutamine amino acid in sequence. And you apply glutamate, |
|
| 48:25 | mike ramallah glutamate is the stimulus. you have these cool patch clamp and |
|
| 48:32 | channel recording techniques and voltage clamp. can control the potential. You apply |
|
| 48:38 | them, you record a very strong current and you apply glutamate and you |
|
| 48:44 | a slightly different experimental setup, you significant calcium current and in edited versions |
|
| 48:52 | glutamine gets replaced by arginine. You the same experiment with glutamate sodium currents |
|
| 49:01 | there. But when you apply glutamate currents are no longer there and it |
|
| 49:09 | seem pretty radical that a single amino in this huge three dimensional structure, |
|
| 49:21 | one break out of the wall renders channel unable to conduct calcium and calcium |
|
| 49:31 | very important for the south. Not much in the membrane potential changes because |
|
| 49:35 | we talk about action potentials, resting were talking about action potentials, we |
|
| 49:40 | about sodium and potassium. So that that the major flux is in the |
|
| 49:47 | of potential because of sodium and potassium little bit due to chloride but not |
|
| 49:53 | to calcio and because calcium serves a function that doesn't necessarily influence and change |
|
| 50:01 | neuronal number of potential as much as intracellular activity. Once enough calcium gets |
|
| 50:09 | it can either influence neural transmission or can activate secondary messengers inside the |
|
| 50:15 | In fact calcium itself is also a messenger. And sodium and potassium don't |
|
| 50:21 | those features. Their charge carriers calcium some charge two plus it contributes a |
|
| 50:29 | bit of that charge difference across plasma but has other significant functions. So |
|
| 50:37 | my reputation transmitters. Okay so I like sarah not necessarily but you would |
|
| 50:56 | less calcium. So if you have system where you have to both conduct |
|
| 51:03 | that means that cell is gonna get through both of these channels. And |
|
| 51:08 | different functions intracellular early. And if don't if you just have one, |
|
| 51:20 | that make sense? Then you have one source in those cells. So |
|
| 51:26 | it's an empire that is that is then oh you're only getting half of |
|
| 51:33 | or what the other cell is It doesn't matter. You have ample |
|
| 51:36 | . D. A. Channels but flux of calcium is not as abundant |
|
| 51:40 | those types of cells that influences their regulation the cellular signaling cascades and the |
|
| 51:49 | tiny says they can bind to a second bind to inside the cells. |
|
| 51:58 | I am the tropic everything that we about is I in the tropics so |
|
| 52:02 | we just mentioned minimal tropic. So an M. D. A. |
|
| 52:07 | ample kind an M. D. receptors. This is measurable tropic glutamate |
|
| 52:12 | . So there are glutamate receptors that not channels and binding of a ligand |
|
| 52:20 | this medical tropical interceptor will actually activate protein complex. We already mentioned that |
|
| 52:27 | this is one of the pathways of formidable tropical glutamate receptors is is the |
|
| 52:34 | of medical tropical ultimate receptor and its protein and complex can turn this molecule |
|
| 52:41 | . I. P. Two into different molecules. So this is another |
|
| 52:45 | is that you have a divergence of activity. You have one glutamate |
|
| 52:52 | one G protein coupled receptor. Motorboat glutamate receptor the same glue or |
|
| 52:59 | And then all of a sudden you and you have two signaling pathways inside |
|
| 53:05 | cell. Because activation of that deep broke up P. I. |
|
| 53:09 | Two through possible life A. Into I. P. Three and |
|
| 53:14 | . A. G molecule. A. G molecule. Diacetyl glycerol |
|
| 53:19 | membrane bound and is affecting protein tiny in the cellular level. And |
|
| 53:27 | P. Three nostril triphosphate will bind I. P. Three receptors on |
|
| 53:35 | and the plasmid, ridiculous um and and the plasmid particular contains high level |
|
| 53:42 | of calcium and binding of I. . Three to this I. |
|
| 53:46 | Three receptor calcium channel will allow for internal stores of calcium to be released |
|
| 53:54 | the cytoplasm. So you're talking about this is a third way that you |
|
| 54:02 | increase calcium intracellular early. So the would have all of these different strategies |
|
| 54:08 | calcium and through an M. A. Some ample channels Race calcium |
|
| 54:15 | early without any channels. Because there intracellular stores full of calcium too. |
|
| 54:23 | again we're not talking about oh you a lot of calcium inside the |
|
| 54:28 | Therefore remembering potential is 20 million volts . It's not it's it's really more |
|
| 54:33 | the signaling it happens intracellular early. kindness is the versus phosphate. Asus |
|
| 54:42 | is calcium co module and canes for it's one of the kindnesses that calcium |
|
| 54:47 | activate. And kindnesses will force for late molecules and other receptor channels that |
|
| 54:55 | add appeal for greed and phosphate. will defrost for a late that will |
|
| 55:00 | the P. O. For group a lot of times post correlating receptor |
|
| 55:05 | nearby channel may influence its function and or keeping that receptor channel open longer |
|
| 55:13 | phosphate stations or defrost for relating a of times means closure or cessation of |
|
| 55:20 | activity that is driven by P. by phosphor relation. So phosphate basis |
|
| 55:25 | kindness is so inside the cells you a number of hospitalizations and kindnesses that |
|
| 55:33 | always active and they're competing against each and they're somewhat specific and they're somewhat |
|
| 55:40 | specific inside the side of class but levels are are fairly uh well regulated |
|
| 55:50 | . So when we look at the protein coupled receptors they're no longer this |
|
| 55:56 | M one through M four sub units we talked about for ample receptor Uh |
|
| 56:02 | typically uh seven trans membrane subunits There's no channel for ligand binds it |
|
| 56:19 | then G protein gets activated. Acetylcholine muscular receptors which are measurable tropic. |
|
| 56:28 | has medical tropic glutamate receptors. Gaba measurable tropic Gaba B receptors, serotonin |
|
| 56:35 | norepinephrine and catholic cannabinoids E. P. That all have metabolic tropic |
|
| 56:43 | . That is not to say that it doesn't have to tropic receptors which |
|
| 56:47 | talked about in a tropical receptors. is not to say that Gabba. |
|
| 56:50 | is both the tropicals trump. Acetylcholine both the tropic in metal shop. |
|
| 56:57 | then there are certain substances that truly serotonin dopamine, norepinephrine and catelynn cannabinoids |
|
| 57:04 | A. T. P. They're acting through medical tropic. So certain |
|
| 57:12 | will act through ion a tropic and tropical receptors and other chemicals will only |
|
| 57:17 | metabolic tropic receptors not channels. Yaba the major inhibitory neurotransmitter of the |
|
| 57:30 | Gaba will bind to Gaba receptor This is Gaba A receptor and this |
|
| 57:39 | different from Gaba D in your uh supporting documents. You have Gaba |
|
| 57:51 | I'm also reminding that you have these are alluded to you This one |
|
| 57:59 | D. A. And this is information where we took the figures for |
|
| 58:07 | nomenclature and I don't need you to the nominee cultures. It's really just |
|
| 58:12 | how there are different systems and how these portions are important more about the |
|
| 58:19 | and antagonists and different portions of ligand domain versus the uh iron channel four |
|
| 58:27 | so on. And the figure on . Oh sis is here too. |
|
| 58:34 | when we come down to an D. A. And glutamate, |
|
| 58:40 | also have Gaba. Gabe's amino acid as the primary inhibitory neurotransmitter in the |
|
| 58:47 | . Major inhibitory neurotransmitter in the spinal is not Gaba really. He wrote |
|
| 59:01 | interesting for all the book says, I seen so is just saying that |
|
| 59:11 | also in the spinal cord even though and a no this is that's maybe |
|
| 59:22 | could interpret it that it sends the inhibitor signal to the spinal cord but |
|
| 59:27 | says major in the spinal cord which why I say it's just interesting. |
|
| 59:38 | let's let's okay so uh this is is a homework question. Yeah. |
|
| 59:52 | a second because they say the primary the brain and they say oh primary |
|
| 59:59 | major primary it's but it's slicing that's major I think saying is there is |
|
| 60:13 | a difference between primary neurotransmitter in Okay here's a homework question. The |
|
| 60:25 | question now. Oh yeah I mean we'll answer it together because I was |
|
| 60:32 | what somehow overlooked the first sentence in . I had this up for like |
|
| 60:36 | or three years now. Never like attention the first sentence I guess you |
|
| 60:42 | . But okay primary functions between neurons binding post synaptic Gaba receptors which modulate |
|
| 60:49 | channels. So some of the Gabba , ion channels and others will modulate |
|
| 60:55 | channels hyper polarizing the cell, inhibiting transmission of the action potential. We |
|
| 61:00 | agree with that clinical significance of Gabba be underestimated disorder and Gaba signaling is |
|
| 61:07 | in multitude of neurologic and psychiatric modulation of Gaba signaling is the basis |
|
| 61:13 | many pharmacologic treatments in neurology, psychiatry anesthesia. Okay so in general we |
|
| 61:20 | start delving into this concept today. even more so next lecture we have |
|
| 61:28 | and inhibition. So major excitation is majors inhibition. Gaba, why are |
|
| 61:33 | saying that Gaba is such a target neuro pharmacological treatments. We also talked |
|
| 61:40 | how an M. D. A is also target but Gabby is for |
|
| 61:44 | reasons. Typically when there is an of excitation and inhibition is because there's |
|
| 61:50 | little inhibition. Excitation is not being and in general everything that will activate |
|
| 61:58 | receptor is going to be inhibitory which going to be a sedative effect and |
|
| 62:06 | static effect on the brain and the . So you have a synthesis you |
|
| 62:16 | released, we haven't gotten their degradation here is the most important to major |
|
| 62:23 | receptors. Gaba and Gaba. Gaba . Is ion a tropic. |
|
| 62:32 | Yeah bobby is a metal tropic G coupled receptor increases post synaptic potassium |
|
| 62:41 | So if Gaba is working through Gabby is working through increasing postion optic |
|
| 62:51 | and decreasing pre synaptic calcium. So we have to, this is |
|
| 62:57 | little bit complicated, don't worry about . So but it's not really. |
|
| 63:07 | is very interesting due to extra selling of florida being lower than intracellular levels |
|
| 63:13 | developing brain. Gaba has excited to in the fetal and neonatal brain. |
|
| 63:20 | there's reversal potentials they can influence a and Gaba is actually excitatory in the |
|
| 63:30 | . So developmentally first you have an . D. A. Synopsis that |
|
| 63:34 | silent and Gaba that can be It's the opposite of what happens in |
|
| 63:41 | brands. Of course it talks about lot major inhibitor an urgency that the |
|
| 63:49 | cord again wow we'll have to look that and revise talks about many different |
|
| 64:01 | . But for us what's important is Gaba binding will open this channel and |
|
| 64:14 | is going to come inside. So you remember finding a blue timid two |
|
| 64:24 | them D. A. or amper the influx of sodium in calcium and |
|
| 64:33 | of sodium we had deep polarization we E. P. S. |
|
| 64:40 | Excitatory post synaptic potential one Gaba by Gaba A receptor it will allow for |
|
| 64:56 | of chloride which will make the membrane negative and will cause an I. |
|
| 65:05 | . S. P. Or inhibitory potential. Mhm. So person optically |
|
| 65:13 | can have Gaba A. And D. A. And ample |
|
| 65:20 | You also can have Gabby. So A will increase the level of flora |
|
| 65:28 | like other receptor channels and non receptors are channels. Gaba receptor has multiple |
|
| 65:39 | sites for different substances. Ethanol or will bind together or something Benzodiazepine. |
|
| 65:49 | we will talk about benzodiazepine as one the most common anti epileptic medications. |
|
| 65:54 | we talk about epilepsy also binds to barbiturates bind to Gavin. There are |
|
| 66:03 | bind together. What do these things in common benzodiazepines? Barbiturates, ethanol |
|
| 66:09 | sedative they increase the levels of inhibition then is a common pharmacological drug. |
|
| 66:20 | is alcohol is a common recreationally drug the effect of both can be quite |
|
| 66:29 | . So that means that a person is taking anti epileptic drugs and high |
|
| 66:35 | that are team may feel drunk literally drunk like uh and that's because it's |
|
| 66:45 | the same receptor. So um yeah would be um metodo tropic. So |
|
| 67:00 | since we set up the theme of A. And B. And we |
|
| 67:04 | up the theme with psychotropic versus medical and glutamate. Now it's easier. |
|
| 67:11 | what's more complicated what's more interesting is seems to be more functions related to |
|
| 67:18 | B physiological. So Gaba it's pretty Gaba binds to Gaba A. And |
|
| 67:24 | goes in and you have hyper What about Gabba being and we'll put |
|
| 67:32 | of this in the perspective in the Gabby is measurable tropic. Gaba binds |
|
| 67:41 | this receptor and can do two things can open potassium channels. So if |
|
| 67:47 | open channels this is outside and this inside and potassium is leaking out. |
|
| 68:02 | means that inside of the number eight becoming more negative so it causes the |
|
| 68:08 | polarization and that is happening fast in . And through another mechanism Gaba B |
|
| 68:19 | activation can block calcium influx pre synaptic . So when we talk about uh |
|
| 68:28 | that it Gaba signaling as those functions described in here and it shuts down |
|
| 68:42 | calcium influx. What do we need for? We're not changing much of |
|
| 68:48 | member and potential with calcium. We calcium too release neurotransmitters and to have |
|
| 68:57 | of this intracellular signaling cascades that we about. Yabba A. Is the |
|
| 69:06 | I PSP and Gaba B. Is late I. P. S. |
|
| 69:09 | . And I'm gonna come back and this in the next lecture because I |
|
| 69:14 | to review the slide with you guys briefly and then we're gonna move into |
|
| 69:20 | inhibitory networks and some rules by which operate. But this diagram is something |
|
| 69:26 | you should study and something that you understand. Well because it has pretty |
|
| 69:32 | everything that we talked about with the of ample channels. So let's look |
|
| 69:39 | , what's happening. So this is synapse says Gabba. That means it's |
|
| 69:44 | Gaba is being released and when Gaba to Gaba A, this is Galba |
|
| 69:54 | blue chloride goes in and you have polarization. But the same molecule Gaba |
|
| 70:01 | post synaptic li buy into these little here. Gaba bees and those Gaba |
|
| 70:08 | posson ethically can also open potassium and more hyper polarization, hyper polarization and |
|
| 70:17 | polarization. So early I PSP component A. Is chloride and late component |
|
| 70:26 | I PS PS gobbledy because metro tropic activation takes some time 10 20 milliseconds |
|
| 70:32 | so delayed for the actual process and of the potassium channel and further hyper |
|
| 70:40 | Gaba as it gets released. Also synaptic alie on the inhibitory neurons as |
|
| 70:47 | B outer receptors or auto receptors. they will bind to Gaba B |
|
| 70:54 | Pre synaptic lee will regulate the amount calcium calcium is necessary for neurotransmitter |
|
| 71:01 | So Gaba hyper polarizes the cell but also can control itself by saying I'm |
|
| 71:09 | going to release more of this So if there's a lot of gaba |
|
| 71:14 | that's coming around here. It's now that I'm not going to release any |
|
| 71:19 | of this. It's auto regulation of own release here nearby. We have |
|
| 71:25 | glutamate excitatory synapse glutamate is being released but glutamate pre synaptic terminals. They |
|
| 71:35 | have pre synaptic gap to be And if there's a lot of Gaba |
|
| 71:41 | and this Gaba actually spills over it activate Gaba B receptors, shut down |
|
| 71:46 | of calcium and shut down the release glutamate on the pre synaptic glutamate |
|
| 71:54 | So gabby can regulate the pre synaptic release and pre synaptic gather roots both |
|
| 72:02 | the receptors. When glutamate gets We know will bind and planned an |
|
| 72:08 | . D. A. Will cause . P. S. P. |
|
| 72:10 | know that N. M. A receptor is a large source of |
|
| 72:15 | source of calcium influx calcium through interactions calcium, co modular lint and through |
|
| 72:23 | through Gabba B. And through this Jalin onto the potassium channel can open |
|
| 72:30 | synaptic potassium channel. This will cause polarization positive charge leaving which will then |
|
| 72:40 | start the deep polarization causing hyper polarization will block the NMDA receptor activity without |
|
| 72:50 | polarization. You have magnesium block. here it's Gaba B. That's regulating |
|
| 72:59 | synaptic glutamate synapse through the secondary messenger through calcium. So calcium again plays |
|
| 73:08 | of an important role in regulating inter activity rather than the member in potential |
|
| 73:21 | . So all of these things are good things to review here. When |
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| 73:25 | come back. Next lecture we will up where we left off with this |
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| 73:30 | , we'll talk more about specific antagonists Gabba Gabba B. And then go |
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| 73:36 | talking about the circuits and the seizures . In addition some rules by which |
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| 73:41 | circuits learn uh the brain rhythms and the plasticity. Uh and I'll bring |
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| 73:50 | supplementary material to read for plasticity. of it I may be uploaded |
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| 73:56 | but I have one really good book that I well uh share with you |
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| 74:07 | on synaptic plasticity. Uh because it's good way of explaining that that I |
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| 74:14 | the way it's been explained in this money. Alright, so we'll see |
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| 74:19 | all on |
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