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00:02 So this is lecture 13 of neuroscience I'm on Uhh video points. I'm

00:08 you that all of your materials have there. I think that now you

00:13 see that there is a display of on most of the lectures so you

00:17 scroll through the slides and literally within to 10 minutes to remind yourself all

00:23 the material that you studied the lecture or a week before you can review

00:28 two lectures for example. So we in great detail the common ergic signaling

00:34 Colin ergic system and you will be for all of the enzymes involved in

00:40 , degradation and all of the details we discussed, including Alzheimer's medications that

00:46 statistical in history's inhibitors and such. so we talked about distinguishing the neuro

00:56 junction from the central nervous synapses. we said that neuro muscular junction have

01:03 very powerful inflate potential and the single will release enough neurotransmitter will generate strong

01:10 of the post synaptic response in the muscle cell for it to produce an

01:14 potential and contract the muscle fiber. in the central nervous system we have

01:21 small E. P. S. . S excited her personality potentials very

01:26 I PS PS. And they sort cancel each other out. And so

01:30 have to have a significant enough excitatory significant enough number of excitatory synapses to

01:38 activated in order to evoke person optically response involves synaptic response. And we

01:48 about I wanna tropic versus Meadowbrook tropic . Last lecture we looked at the

01:56 arctic neuro pharmacology, distinguishing nicotine IQ mask your enic acetylcholine receptors. And

02:04 at the neuro muscular junction you will have nicotine acetylcholine receptors and only and

02:09 to have a positive response. Deep in the muscle. And as we

02:14 masculinity receptors can actually cause a different effect at the level of the

02:20 So if the acetylcholine binding to nicotine receptor will cause deep polarization binding of

02:29 cyclical into masculinity, G protein coupled will cause a hyper polarization because through

02:36 jew protein complex it will open the channel so which one will win.

02:42 don't know. But temporarily nicotine acetylcholine will win the polarizing missile and then

02:49 some delay because of the metal bar signaling. Some tens of milliseconds

02:55 You will engage another metaphor tropic potassium channel opening and hyper polarization instead

03:02 deep polarization. So we also talked cata cola means uh and mono means

03:10 general. We talked about serotonin and talked about their breakdown so subtle Colin

03:18 broken down in the synaptic cleft by asteroids. Mono means okay the other

03:25 cola means in serotonin actually re uptake back into the present at the cleft

03:32 then they're neutralized by oxidation with Amine oxides which hangs around the

03:39 the membranes of the mitochondria mitochondria are prevalent in these pre synaptic terminals.

03:46 need a lot of mitochondria to generate and a tPS needed in order to

03:51 and prime the vesicles at the pre active zones. And this is the

03:56 function is that the mitochondrial membranes will laden with this enzyme that will be

04:05 cata cola means and rendering them basically them down further than it takes time

04:14 re synthesize them and then upload them . So we know that this is

04:22 different from the seed alkaline, although in the way of the neural transmission

04:29 reloading of the of the bicycles and . The neuro peptides are different because

04:34 in secretary Granules as we discussed So we discussed serotonin and we discussed

04:46 pharmaceutical preparations and drugs and illicit drugs would target some of these transporters for

04:53 cola means signaling or serotonin signaling. talked about in the cannabinoids talked about

05:01 ways of studying neurotransmitters and neurotransmitter You can study different components using

05:11 immune, artistic chemistry, radioactively labeled sensitive hybridization. Your transmitter mimicry with

05:19 electrode dialysis or neurotransmitter mimicry with UNQ of the neurotransmitters of interest using laser

05:30 . It's very fast speeds with very spatial resolution. So all of these

05:35 may show up asking you some questions the quiz or on the exam.

05:41 talked about synaptic integration and how does soma here integrates the information that comes

05:49 and we talked about the spatial summation will immediately cause a very large response

05:57 optically and we talked about the temporal which will cause a much larger response

06:03 not as large as a spatial but that post synaptic response due to

06:09 temporal summation will be prolonged, still any further inputs that would be excited

06:16 into the cell. Or dipaula rising the cell, still having a positive

06:21 facilitate ori effect on those talked about length constant which is essentially the distance

06:28 the peak current injection here and as measuring the speed current injection right here

06:34 the site of the injection, You 100% maximum current. And how what

06:40 , How far can this current travel dendrites And Soma is because they are

06:45 myelin ated. There's no regeneration. will be certain current loss over distance

06:54 if the current is small it is the distal distal dendrite, that current

07:00 travel and by the time it reaches will be negligible and size, that

07:05 polarization or even hyper polarization. So distance At which discouraged from the maximum

07:14 goes down to its 37% value. distance is referred to as the length

07:20 lambda. And the long length constance promote the flow of that current over

07:27 distances and short length constance would result that current in that curve being steeper

07:34 that current dying down over a shorter . We also talked about inhibition and

07:46 inhibition and in general the principle that and inhibition and excited or an inhibitory

07:53 will be competing for the attention of cell that is integrating the signal and

07:58 post synaptic cell and that if you strong inhibitory inputs that are close to

08:04 selma and remember the selma is where information is integrated. It's an integrative

08:10 of the neuron and the axon initial is where the action potential is

08:16 So if you have strong inhibition close the selma, to these regions,

08:21 inhibition will negate the deep polarization or excitation that might be generated more

08:29 One of the ways that does it does it through what we call

08:33 shunting inhibition. Then we moved on reviewed again all of the neurotransmitter systems

08:40 we were talking about. And I that we talked about metabolic tropic signaling

08:47 we talked about metabolic tropic acetylcholine receptor in this case. And this is

08:54 example of how metabolic tropic acetylcholine receptor will cause the opening of the potassium

09:04 and the potassium channel opens. You , there's a lot of potassium inside

09:07 cell that positive ion positive charge will the cell and the cell will be

09:13 polarized. So this is the physiological and the molecular mechanism behind the medical

09:23 signaling glutamate and gaba the major excitatory inhibitory neurotransmitters and glutamate, as we

09:32 as a part of this tripartite synapse that astra sides real cells control the

09:42 and cycling of glutamate and can affect activity between the tunes are connected

09:49 So we looked at an example where am the tropic. Acetylcholine is de

09:56 , minimal tropic is hyper polarizing. different mechanisms and they can be co

10:01 and co expressed on the same cells the same nearby patches of the

10:07 You can also have competition amongst the tropic signaling receptors. And such competition

10:14 described in the case of norepinephrine, beta norepinephrine receptor having Gs stimulatory G

10:22 and promoting the production of cycling campion kindness. They pushing to produce more

10:30 on the opposite side here binding off to alpha two receptor with pulled the

10:37 away from producing more of the cyclic and more of the protein kindness.

10:44 recall that kindness is famous for elit they contribute this P. 04

10:49 They donated two receptor proteins and quite these P. 04 groups make these

10:58 and channels more active and phosphate aces phosphor aly the uh the pac man

11:05 chews up the P. 04 group for late and quite often defense correlation

11:11 lead to reduction and function along that protein or that pathway. So inside

11:17 cells you have these layers and levels kindnesses and prospectuses signaling with certain spatial

11:27 of course dependent on the location of G proteins and their complexes. So

11:35 will ask you questions on the exam on potentially quiz on some of these

11:41 nuclei in the brain stem. So that norepinephrine was produced by local

11:48 The blue nucleus, interestingly enough when cells are exposed and norepinephrine cells are

11:56 to oxygen to actually turn blue so does appear bluish under a microscope.

12:03 serial lius. These are the these are the only soulless in the

12:10 cns that will produce norepinephrine and then axles from these selma's, what we

12:19 are very diffused and they're often called sprinkler systems of the cortex because they

12:28 diffuse lee project those axons and diffused Sprinkle neurons and circuits in the cortex

12:36 norepinephrine. If you're talking about serotonin will come from the raft nuclei.

12:43 will get sprinkled and so we are to get to the specificity of this

12:49 of course the specificity and the specificity the response depends on what these post

12:54 neurons that are being sprinkled or open and express. Do they express beta

13:01 by beta stimulatory or alpha two Different subtypes will express different subtypes of

13:08 medical tropic receptors. Also different levels these medical tropic or anna tropic

13:14 So recall that I want to stay for a second if you were for

13:29 to take local Sibelius out there would be in northern africa synthesized anywhere else

13:37 the brain. So this is how confined Now if you were to take

13:42 chunk of cortex out there would still gaba and glutamate synthesized everywhere else where

13:51 didn't remove that jump, you So so this is this is really

13:55 difference in what I said is if think about excitation, let's say it's

14:02 . Inhibition is black, then the systems and these neurotransmitters, acetylcholine mono

14:08 other things. They add all of color or grayscale if you may to

14:13 black and white and make the whole in the brain more interesting. The

14:19 by which neurons learn can change with neuro modular torrey substances and they can

14:25 the balance of excitation and inhibition in brain. And if you have the

14:30 imbalance along serotonin ergic pathways. Ah you're looking at the neuropsychiatric disorders,

14:40 disorders, anxiety disorders, this is disorders that would be associated with those

14:47 and those camera films. If you're at loss of acetylcholine neurons and Colin

14:52 central tone and aging population, you're at a concern of Alzheimer's disease.

15:03 you look at Parkinson's motor neurological disorders have motor dysfunction component. Ah There

15:13 be dopamine dysfunctions. You know, disorders like schizophrenia also has a dopamine

15:20 and one of the dominating hypothesis of is imbalance of dopamine receptors you want

15:27 D to the ratio of those and cannabinoids are different because they're not packaged

15:34 vesicles and what happens is that they produced on demand, their lipid soluble

15:41 signal retrograde lee. That means they from post synaptic side into the pre

15:46 terminals and through the G protein coupled at the pre synaptic terminals that are

15:52 with the CBD cannabinoid receptors one and control the release of glutamate and gaba

15:59 the pre synaptic terminals. So you when we can have notes, balanced

16:03 levels of the excitation and inhibition whenever levels increase and there's too much there's

16:10 much stress, there's too much of for example, too much glutamate can

16:16 to what is called glutamate. Excitatory . Too much glutamate will mean too

16:21 calcium prison optically. That means a of action potentials. A lot of

16:27 prison optically. A lot of glutamate . That means a lot of calcium

16:31 optically and glutamate excited toxicity. Too excitation can lead to toxicity. Too

16:38 excitation can lead to too much calcium . If it's unregulated inside the

16:44 most of the calcium in the cytoplasm not floating around freely gets bound up

16:49 all of these calcium calculators and calcium proteins. But you have too much

16:54 that calcium go up. It also be toxic but also can upset the

17:00 of these intracellular molecular signaling cascades and promote calcium induced calcium release from the

17:07 and turn on this vicious cycle. having molecules like cannabinoid receptors having other

17:14 pre synaptic li like a dentist in having pre synaptic aly gaba B receptor

17:20 you'll see later today helps regulate the synaptic neurotransmitter release. But in particular

17:26 the cannabinoids, the gasses and now C. O. They will function

17:30 this retrograde fashion and control activity on pre synaptic side despite their production on

17:36 pasta topics side a lot of times can view this as a negative feedback

17:41 . So negative feedback like an air . Right? So too much

17:46 You turn down the heat you turn in the sea and this is the

17:53 important function of the other cannabinoids in brain. Mm hmm. So we

18:05 here. Okay do we discuss things cannabinoids? Deep polarization induced suppression of

18:13 for control of gaba release. Deep induced suppression of excitation for control of

18:20 release. We also saw that the excitatory neurotransmitter glutamate is one enzymatic reaction

18:29 . Deeper box elation by the atomic , deeper box list removal of this

18:34 group here into the major inhibitory neurotransmitter . You'll also learn today that when

18:42 first studied glycerine in the spinal we said that listen is the major

18:48 neurotransmitter in the spinal cord. It's by the inhibitory into neurons in the

18:55 cord. But today you will learn glycerine is also involved and excited to

19:03 signaling in the C. N. . In the in the high order

19:10 all of the inhibitory into neurons and and the Hippocampus. This varieties of

19:19 that we were looking at 21 different of inhibitory neurons. They will all

19:25 for God what time of casa speaker ? They'll all be still containing different

19:34 cellular markers. They'll still have their anatomy, their dialects and actual

19:40 All the good things that you learn they will all be released in Gaba

19:46 they might still be co expressing some the peptides. So they will be

19:51 Gaba and some of the statin for so they can co express and co

19:58 these. Remember there's differences when you the neuropathy ties in the whole bio

20:04 trafficking and release of them that is from the secular mechanisms. Glutamate gets

20:14 into neurons and so this Gabby get so they have transporters into neurons and

20:21 they have transporters into vesicles. When think about interesting therapeutic strategies, these

20:26 very difficult therapeutic strategies. But can affect the loading properties after the secular

20:35 transporter? I'm not saying there's an to it. I don't even know

20:41 there is a drug there but so we've learned that we control most of

20:45 things that the synaptic cleft by degrading chemicals in the synaptic cleft war by

20:51 re uptake of these chemicals prison optical more difficult by chemical neurological treatment strategies

21:01 concern While let's just affect let's say transporters can we do that instead of

21:10 we actually block something out? So , remember when you think about the

21:16 systems it's a system from pre synaptic loading release post synaptic effect degradation of

21:25 synaptic cleft and recycling and so a of the a lot of these parts

21:32 be employed for therapeutic strategies and drug . So let's talk about we don't

21:40 Nero pharmacology. These are three iron tropic glutamate receptor channels the major ones

21:50 the C. N. S. Tampa and MGmt Nate glutamate is an

21:55 to all of them. Glutamate is endogenous agonists that we produce to all

22:01 them. And then you have chemical that will distinguish them Bubble Banter Apple

22:09 in MD 80 and MDA. Kinda kinda interceptors they will also have their

22:15 distinct antagonists as well. So what the pharmacology and how is this

22:23 P. S. P. So when there is glutamate release and

22:29 here are these little green molecules when gets released from the pre synaptic terminal

22:38 will bind to both Tampa and an . D. A receptor is by

22:42 way ample and Canaanite are quite often together because of their similarities and their

22:48 and uh and responses and an D. A. Is there's a

22:55 a bit of an oddball so the receptors are shown here in blue and

23:01 receptors are shown in pink and these molecules are glycemic molecules. So when

23:11 goods released and glue mate will bind both happen, NMDA receptors, Albert

23:22 will actually open immediately and they will conducting sodium inside causing the initial deep

23:31 of this excitatory post synaptic potential. looking on the post synaptic cell.

23:36 post synaptic responds. How does The PSP comes about? What

23:42 This is a collective change in the and potential E. P.

23:46 B. This is Andy PSP excited passing up with potential. We now

23:55 that there is a number of glutamate . So what we know is this

24:03 phase of E. B. Be is generated by AMFA receptors and

24:12 late phase the E. P. . B. It's generated by an

24:18 . D. A receptors. So M. P. S.

24:22 Is a composite response of deep polarization re polarization through both Tampa and an

24:33 . B. A type channels. difference is the following. While glutamate

24:39 to ampara reception, it will immediately the upper channel cause the influx of

24:45 causing the initial depressurization and I'm the receptor it's not going to open immediately

24:53 N. M. D. A has a magnesium block. In fact

25:00 has both magnesium and zinc blocks. there's two cat ions. Mg two

25:11 Magnesium two plus that is blocking the one that is blocking this poor after

25:19 receptor channel and the only way that channel can open is if you remove

25:27 magnesium from from this channel and in to remove the magnesium the membrane potential

25:36 to de polarize. So what happens when glutamate initially binds the ample

25:44 it d polarizes the numbering potential that for the magnesium to be removed from

25:51 NMDA receptor. Then an M. . A receptor opens. And as

25:56 can see an M. D. receptor will be conducting sodium inside also

26:02 de polarizing the self but also most calcium. It's very important source of

26:10 of calcium through NMDA receptors important for cascades, important for learning important for

26:17 plasticity that we've discussed from the beginning of course the re polarization through both

26:24 channels will happen when potassium subsequently too polarization. The potassium will now leave

26:31 cells re polarizing um to this initial in potential before the BsB. So

26:39 membrane potential of minus 65. An . D. A receptor has magnesium

26:45 And only if you d polarize these to -40 -35 -30. That's when

26:53 NMDA receptors will open. Two. there are distinct differences. This does

27:03 make an M. D. A um edible tropic receptor. They're all

27:07 tropic receptors. This is an example on the right of metabolic tropic glutamate

27:14 which is linked to g protein complex signals through a molecule called phosphor

27:20 A sea of PLC. So an . D. A receptor is a

27:26 its eye on a tropic. This quite often missed by students. They

27:31 that because ample opens immediately it's on tropic and because an M.

27:35 A. Has a magnesium block it's of a tropic. It's not metabolic

27:40 is only if it's linked to jupiter complex. These receptors are channels Tampa

27:48 India receptors are channels G protein complex are not channel. So binding of

27:55 and metabolic tropic glutamate receptor will not the channel in the middle of the

28:02 receptor because there is no channel it just activating downstream cascades through the jew

28:08 complex. So now you have non . M. D. A.

28:12 is an MBA. And kind And have certain differences between 20 PICO Seamus

28:18 that? We talked about conductance is and we talked about relevant scales of

28:24 is So this is how much a ample channel will conduct. About 20

28:29 emails of current An M. A receptor on the other hand will

28:34 50 PICO cements. So who has conductors who can put in more positive

28:41 as an M. D. A . But you have to wake it

28:44 you have to de polarize the cell remove the magnesium block. They have

28:49 own antagonists or specific blockers. And it receptors are blocked by a substance

28:56 C. N. Q. And an M. D. A

28:59 is blocked by a substance called a . So this is important. We're

29:06 learning agonists. Remember for nicotine nick nicotine, Azizi mascara nick, there's

29:14 mask urine for civil Colin receptors. the antagonists, nicotine IQ is

29:23 masculinity is atropine, we use all questions. These are agonists again.

29:31 is easy and it is an An M. D. A.

29:34 an M. D. A. an agonist kindness, kindness is an

29:37 . Glutamate is an agonist for all of them. It's natural endogenous substance

29:42 bind them differently and then they have own antagonists. So mostly will be

29:48 for knowing this an M. A receptor antagonist because it shows up

29:51 a very important graph that we're about discuss. NMDA receptor is dubbed as

29:57 coincidence detector because it coincidentally has to the release of the pre synaptic neurotransmitter

30:06 binding of that neurotransmitter glutamate to the of the truck and post synaptic deep

30:11 which gets generated through ample receptors. it only gets engaged if there is

30:18 of the post synaptic deep polarization. it's coincidentally detecting pre synaptic activity.

30:24 and post synaptic activity deep polarization only it engages. That's very important in

30:31 feature coincidence detection feature an influx of through an MD. A receptors very

30:39 for plasticity for strengthening the synapses for the synapses more efficacious stronger and learning

30:50 the brain. Now an M. . A receptor because it takes time

30:57 it to open up is responsible for late portion of the E.

31:03 S. P. And Apple receptor responsible for the early portion of the

31:09 being most of the AMP A non receptor sample key Nate will allow for

31:17 of sodium and the flux of potash . But all in MD A receptors

31:24 allow for influx of calcium. So some complicated receptors but all in NBA

31:33 they pump calcium in this is where comes into play. Glycerine is a

31:42 factor that the NMDA receptors. That that glutamate when it binds to the

31:50 receptor. If glycerine is there is co factor it makes sure that this

31:55 of glutamate, NMDA is really good strong and in the absence of glycerine

32:00 a co factor this is in the not in the spinal cord. The

32:05 of glutamate is not as efficacious. N. M. D. A

32:10 . And so like I seen in inhibit their into neurons and the spinal

32:16 is inhibit their neurotransmitter. But when binds to NMDA receptors in the CNS

32:22 a co factor. Okay this is binding sign for magnesium There's also you

32:30 see there's a binding side for zinc titanium zinc two plus. And these

32:37 receptors will have many different binding It's a site for therapeutic targets for

32:46 drugs. It is also can be by illicit drugs and and then the

32:55 receptor one it is over activated by like PCP crystal methane and such can

33:06 not only hallucinations but can induce acute that can become chronic schizophrenia from just

33:14 few or even a single dose of of these very potent drugs. So

33:21 all about the dynamic range of the . This is a great dynamic range

33:27 the system to learn activated with endogenous , maybe some pharmaceuticals to to repair

33:34 system. But if you pull that too far out of its dynamic range

33:41 can happen with illicit drugs that have stronger binding properties to these receptors.

33:48 happens to that rubber band it snaps it's no more so in all of

33:55 systems it's like that serotonin has its dynamic range of functions and the phenomenons

34:02 their own dynamic range of functions. of them have a better set boundaries

34:07 this dynamic range so it doesn't let that string to be pulled too far

34:13 string or rubber others are more susceptible other systems. Chemical systems and receptors

34:21 more susceptible to to pulling and it on the substances of buying to

34:27 Okay and uh MK 21 that I here is an interesting antagonist so some

34:35 will buy into an M. A receptor no matter what whether it's

34:38 or closed MK 80. 1 Is antagonist that will bind to only open

34:44 MD 80 or so. So again what's the difference between closed and um

34:53 interceptor and open an M. A receptor? The confirmation will change

34:58 something that opened up in this protein channel. Maybe there is an opening

35:06 that can receive another molecule and the change another molecule can have access now

35:11 buy into sequence of amino acids from protein. Okay so now we come

35:17 to this concept of voltage clamp. that we can control the voltage,

35:23 can clamp the voltage. And if record and MDA receptor currents and these

35:29 deflections downward deflections and upward deflections is opening And current flux is through NMDA

35:37 and its physiological magnesium concentrations extra cellular you have about $1.2 million dollar

35:45 And at these physiological magnesium concentrations you see at minus 60. There's barely

35:51 opening, there's barely any flux. of these deflections that represent flux through

35:57 M. D. A channel and . D. A channel currents.

36:00 you de polarize the cell to -30 can see that there is a lot

36:05 of an NMDA receptor and it's starting open fairly well. The reversal potential

36:11 equilibrium potential in this case the reversal for an M. D. A

36:17 is zero million volts. Remember what potential is. This is our ivy

36:28 Ivy, this is -60 plus Yeah this is minus one. Yeah

36:39 know out there plus one another up and so This is the reversal is

36:50 mila vaults. Remember we looked at potassium curve I. V.

36:57 this is potassium I. V. . It reverses about -80 million volts

37:04 . Mm hmm. So now you no current flux at zero motive.

37:09 when you de polarize and lock that potential to positive 30 you see a

37:14 more of the flux, positive Very very robust flux. In fact

37:20 seems that an M. D. receptor just by looking at these traces

37:25 recordings prefers to conduct in that opposite in the upward direction. Remember we

37:33 that not all of these I. curves are linear. A lot of

37:39 are rectifying or they have different shapes multiple kind of a bumps if you

37:49 when they're active and when they enacted this on the right there's a physiological

37:55 in which you remove magnesium zero magnesium the system. Now what does that

38:01 ? That means that there's nothing blocking receptor. If there's nothing blocking NMDA

38:07 and you release glutamate boom at minus you see a very strong response and

38:14 30. You see still a strong then at zero you see nothing that's

38:19 the current reverses for an M. receptor and then again you see strong

38:24 D polarized holding membrane potentials. This proves that magnesium block is holding an

38:32 . D. A receptor. So you remove magnesium NMDA receptor can be

38:37 at hyper polarized potentials. This kind a Condition, physiological condition of zero

38:47 will evoke seizures and epilepsy. So you don't have proper levels of magnesium

38:54 proper blockade of an M. A receptor channel and glutamate is

38:58 an M. D. A receptor on check. It will cause way

39:02 much deep polarization that can cause abnormal neuronal networks, abnormal signaling and evoke

39:13 electrical activity. We call seizures or seizures and neuronal circuits. This is

39:19 Model zero Magnesium as an experimental model generating seizure like activity in vitro and

39:28 viva as well. So it's all the balance of that system. You

39:34 that magnesium in there, wow. . And now we're going to talk

39:41 the ivy plots for Ampara Skynet and receptors. So in this case,

39:50 we're doing is we're using voltage we're going from minus 80 minus 42

39:56 20 million volts and we're stopping every or so million volts along the scale

40:03 and we are measuring the early So this artifact here is glutamate release

40:09 stimulation of glutamate. And we're gonna this line here some five milliseconds later

40:17 the glutamate release. And this is be our line that measures the peak

40:22 and the early component of the P. S. P. And

40:26 we're gonna draw a second line The second dash line, let's say

40:31 10 milliseconds later. And that line going to measure the current fluctuations that

40:38 some 20 milliseconds after the glutamate So this way we can monitor the

40:45 component measure the early component and the components. We're using a voltage clamp

40:52 equals Ir we're clamping the voltage therefore measuring the current. This is the

40:58 fluxus, this is an inward current at -80 you can see that this

41:03 current is very sharp with a very recovery. So at -80 if you

41:10 the early component here you have a deflection. Early component -40. Still

41:17 plus 20 is still there. And is the linear line here that represents

41:23 Tampa I. V. Curve. of these triangles here represents the

41:30 Curve for ample receptors. So ample channels and this early component for which

41:38 is responsible is the linear component of . P. S. P.

41:44 it has linear I. D. with a reversal potential at zero military

41:52 aren't you? Glad you learn things I. D. Plots. Now

41:55 will say. Okay that's really interesting when we studied the reversal for potassium

42:01 was acqua Librium potential for potassium It's zero. No evolves for ampara

42:08 . What ions this amp a receptor , it conducts sodium M. And

42:15 out. So now this reversal potential the receptor channels reflects multiple ionic species

42:25 sodium and potassium. And in fact seeing that zero Mela vaults. Remember

42:31 sodium equilibrium potential is positive 55 And potassium equilibrium potential is negative 80.

42:39 actually it's biased toward sodium. The His bias towards sodium because it allows

42:45 sodium to flux in through it has stronger conductive power through sodium, so

42:51 speak. And then when we measure late component at -80 -100 -80.

42:59 are the closed circles here, we're seeing much current. But then when

43:04 de polarize the cell to -55 -15 year. We are seeing now this

43:14 component here. We're seeing this late component and that's an MD. A

43:21 and you can see that NMDA currents disclosed circles are nonlinear. They're reversed

43:28 million balls and they are rectifying in outward direction. Remember the currents at

43:34 negative our inward currents of the positive ampere values are outward currents by

43:43 And the last part of this curve what happens if we apply a

43:49 A PV is N. M. . A receptor antagonists. Remember we

43:54 that there's agonists and antagonists, A is an M. D. A

43:58 antagonist. When we apply a this blue line under the curve is

44:06 . So instead of having this top here. Okay, the late current

44:11 now block the late current and if block the late current with a

44:17 V. You can now see if affected the early components. So the

44:21 or the open triangles is the early . You see that A peavey doesn't

44:26 the early component at all. But a PV blocks the late component and

44:32 are the open circles and so now have essentially zero this line down to

44:38 zero current value. Of course there some residual uh deep realizations and cars

44:45 this is the open circles and instead this nice closed circle shape and

44:49 D. A. Car you know it and you have zero current.

44:54 now this is another demonstration how you use a voltage clamp. Remember how

45:01 Narahashi had the tetrodotoxin and he needed use the voltage plan to isolate sodium

45:07 potassium currents while the Hodgkin and Huxley sodium and potassium current during action

45:14 And then Toshio Narahashi had the toxin had to isolate the sodium current and

45:19 it to definitively showed that it just the sodium current, not the potassium

45:24 . So this is a similar type experiment but now it's within the context

45:29 the I. D. Plots and potentials for these receptor channels that conduct

45:34 potassium and in the case of an . D. A receptor sodium potassium

45:38 calcium understood. Okay so again an . D. A receptor is responsible

45:45 the late current. A PV will that late current. It will not

45:49 the early component at all. And component is the linear component Tampa and

45:56 late component is an M. A. It's a nonlinear component and

45:59 nonlinear because it has a magnesium blockade that magnesium is blocking keeping the current

46:06 zero until the membrane potential D polarizes minus 50 or so. And that

46:12 is now kicked out of an D. A. Receptor. So

46:17 talk about calcium permeability and amping In fact this is very interesting lesson

46:25 you have this very complex sequence of structure which is ample receptor channel and

46:34 M. One M. Two, three and M. Four uh

46:40 And in unedited version if there is . Or glutamate, ample receptors can

46:47 permeable to calcium. But if you this really very long sequence complex sequence

46:54 this one spotted em to replace With our which is argentine, you

47:01 the flux of calcium throughout for So certain ample receptors will not allow

47:07 flux of calcium and certain ample receptors will allow the calcium influx if there

47:15 if they're unedited so to speak. this is an experiment this is glutamate

47:20 . You're measuring glutamate to applying glutamate . This is sodium current and you

47:27 see very strong sodium current following glutamate hmm And this is calcium current through

47:34 M. D. A receptor. you're using voltage clamp don't worry about

47:38 holding potentials. But you know how isolate sodium current, you know how

47:42 isolate castle current and you see both you're using this Q version of ample

47:51 but if you have the r version version of apple receptor, your black

47:57 , you still can see very nice current but now there is no calcium

48:02 through that channel. So this just you how you can take one Chair

48:07 of the building and determine whether that is going to be permissible to calcium

48:13 not major, major not just ion also secondary messenger inside the south on

48:23 ginny. In early development there is an NMDA receptors in the synopsis.

48:29 there are a lot of times referred silence in absence because you need to

48:34 stimulate them very very strongly and activate channels. There's no amperage suffers to

48:40 polarize so they're silent until ample receptors inserted and early during the development a

48:48 of synapses will have an M. . A receptor without anti receptions and

48:52 the composition of those NMDA receptors. have these subunits called an R.

48:57 A and R. To be there be shifting during the development. This

49:01 what's referred to as a not a of receptor ontology nears functional ontology any

49:08 location and activity dependence, ample receptor past and these these receptor subunits their

49:18 changes as a function of the development then as a function of the

49:22 You will have a lot of ample that are located extra cellular early and

49:26 ample receptors may be imported into the sides. Extra synaptic aly I mean

49:33 extra cellular early and they will be into the synopsis. So amber receptors

49:38 move really fast. L. P. Stands for long term plasticity

49:43 long term potentially ation or strengthening of synopsis and influx of calcium and coincident

49:50 by an M. D. A are very very important concept for

49:56 Recall that these are ion a tropic receptors, metabolic tropic glutamate receptor signaling

50:02 this pathway through P. I. . Two that is a membrane bound

50:07 can activate this jew podium complex that now through possible. I pay see

50:13 this molecule into I. P. which is a non hospital triphosphate

50:19 P. Three combined to the eight . P. Three receptors that are

50:26 channels on the smooth ectoplasmic particularly and further intercepted the calcium leads. Okay

50:34 I. P. Three and binding can generate intracellular calcium three. And

50:38 calcium stores the second component of that . A. G. Which is

50:43 absolute glycerol will remain membrane bound and activate another molecule protein kinase C.

50:52 um you have divergence of the pathway the membrane one element going into cellular

50:59 one element remaining membrane bound and uh can activate core module and kindnesses and

51:09 the kindnesses post for a little phosphate defrost correlates. So you will be

51:15 these molecules through the measurable tropic signaling . But this is a pretty common

51:21 tropic ultimate receptor activation. Mhm. Gaba a gobble. When Gaba binds

51:31 Gaba channel, what happens is there a flux of chloride. So when

51:37 binds a chloride channel, Gaba a iron a tropic receptor channel, it

51:42 cause the influx of chloride. You have Gaba be measurable tropic Gaba receptor

51:51 and that can regulate potassium channels and channels. It can open potassium channel

51:58 it can close calcium channels through this and complex. So you have Gaba

52:06 psychotropic Gaba b metabolic tropic receptor, A. As I am a tropic

52:12 and flux in the fluoride will inhibit cell activity will hyper polarize, the

52:17 activity will make it more negative. is the binding of Gaba and this

52:23 a receptor is also target too many different substances, pharmaceutical substances and also

52:33 margarita. At the happy hour ethanol bind to Gaba A receptors. So

52:42 first drink causes a little bit of as well as the person down The

52:49 1, maybe also. And then there is too much activation of ethanol

52:55 inhibition it goes through disinhibition process and the time you're having a third or

53:01 drink, your climbing up and dancing the table all the division was

53:07 So the cycles and the and the effect of alcohol in the brain and

53:13 it changes goes through different stages. this is the receptor that will be

53:18 as the gaba A receptor. Uh benzodiazepines, you will be hearing rap

53:25 . Benzos got some benzos so that are benzodiazepines. So those are pharmaceutical

53:33 and of course you know sometimes they their way in the streets ah the

53:40 because they kind of a slowdown in in the brain inhibit activity in the

53:47 . But benzodiazepines are also very potent medications that are used to boost inhibition

53:56 are very common and still perhaps one the most effective drugs at stopping epileptic

54:04 . Benzodiazepines are very commonly used. when you hear the hip hop songs

54:11 about something else using it for something . Barbiturates um neural steroids also have

54:21 sites to gather receptor Gaba A receptor this case Gaba B. When Gaba

54:31 stood and opens the potassium channel and causes hyper polarization. So if you

54:38 chloride channel you cause hyper polarization and G protein complex if you open potassium

54:44 potassium positive islands, leaving well also hyper polarization. So this is sort

54:51 a before I get to that I look at this traces here where you

54:57 typically you stimulate and you will see excitatory response E PSP. This very

55:03 excitatory response. This is actually from recordings when I was a graduate

55:09 So I would see this very strong . P. S. B.

55:13 it was very sharp and it was by Gaba A. And Gaba

55:18 Because it's conducting chloride. It's trying drive the number in potential too equilibrium

55:24 for chloride. And then Gaba Is hyper polarizing the member and further

55:32 opens the potassium channel and tries to the number of potential. So the

55:41 inhibition is Gaba A. And the inhibition is Gaba B. Gaba B

55:46 be even further hyper polarized. So this case I wanna tropic Gaba and

55:52 tropic are causing the same physiological Fanatical. There's various combinations of these

55:59 that we talked about and what I is actually I would like to probably

56:05 is the last slide and very brief about g protein coupled receptors. I

56:13 leave it actually to the next I'm not going to rush through this

56:17 I would highly recommend that you look this diagram, you won't have to

56:22 it. But it's really really explains lot of things that we talked

56:26 It looks at the glue dramaturgical excitatory . It looks at the Gaba ergic

56:32 synopsis. It has these things that already know post synaptic densities Gabba.

56:39 be potassium channel calcium channel N. . D. A receptor. And

56:43 when we come back next week on we'll put all that we've learned about

56:49 excitatory glutamate ergic signaling inhibitor dramaturgical signaling this diagram. So you understand the

56:57 at the level of these communicating excited inhibitor synopsis. Quickly review the jew

57:04 coupled complex S Types of the receptors you have and then we will move

57:11 c. n. s. so expect. Maybe we'll spend another 15

57:15 20 minutes reviewing and adding some new on Tuesday and then moving into the

57:22 and function of the cns. All , thank you very much. And

57:25 gonna stop the recording and and the here to make sure that I clear

57:30 room on time, Have a good . Everybody remember that. A a

57:38 all happy hour. Don't dis inhibit

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