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00:00 this is mid term to review for and Synaptic transmission communication of 100 billion

00:10 neurons in the brain trillions of You lay out the brain and the

00:16 services like four soccer fields and membrane which is the fabric of our

00:23 These guys here are Monica hall uh Charles Sherington, Camelia gold, you

00:29 course from the past and of the who discovered neural transmission seal Colin by

00:35 the vagus cranial nerve town that goes the cardiac muscle causes the slowing of

00:42 heart rate. An eerie applied the on the naive heart and charlotte saw

00:47 same effect proving chemical neural transmission but also gap junctions, electrical neural

00:54 There's advantages for gap junctions there fast for cells to synchronize and you have

01:00 flux of ions and small molecules. it's secondary messages between the cells and

01:06 you have chemical and electrical neural transmission the synopsis you have access somatic

01:15 accident, sonic and gender didn't ready discussed that acts tectonics and absence.

01:20 don't really affect how to sell the integrative properties but it actually affects out

01:26 properties of the cell where the other actually somatic. An accident riddick,

01:33 affect how the cell is going to that information. Whether it's going to

01:37 an action potential, distinguish between the of typical excitatory around testicle is symmetrical

01:44 inhibit very symmetrical number and differentiations with or vesicles here we talked about that

01:51 things. We talked about the neuro junction. We talked about the employees

01:57 and talked about how the release of cdo Colin will activate. Only nicotine

02:02 receptors is different from the cardiac muscle a skeletal muscle will activate and open

02:08 nicotine acetylcholine receptors will cause very large polarization, employed potential and more than

02:15 million volts and amplitude that deep polarization activate down located here in the genre

02:22 false both educated sodium channels and calcium and generating twitch of a muscle or

02:29 action potential muscular action potential. So high fidelity, very high functioning synapse

02:36 deep polarization At the level of that on here causes a twitch of a

02:42 because of the employee potential or P. being $70 million dollars in

02:47 or larger. So review the neurotransmitter . You have to synthesis transport enzymes

02:53 degrade them and then you have to a whole system plus synaptic aly binding

02:59 ion a tropic and met over tropic systems. We'll come back to this

03:06 but review this that you need deep calcium entry for the exhaust psychosis and

03:15 whole cycle of endo psychosis as Um There is in the synapses in

03:27 cns. There is full and partial . So you should review that uh

03:35 the silicone in signaling. We talked the studio butcher line um and botulinum

03:42 that they interfere with this particular protein binding to the member and protein complex

03:49 therefore with the civil Colin release. this is prison attic person athletically you

03:55 an effect from Taiwan East cobra and will have their effect within the synapses

04:04 affecting a spherical industries. So fast transmission in the brain is mediated in

04:11 cNS, primarily by glutamate excited to synaptic potentials. But the single synapse

04:19 of a single synapse would result in very small deep polarization, about $0.5

04:26 and a half a million. Also opposed to the neuro muscular junction 70

04:30 volts one synapse here is $0.5 So you need to have many different

04:35 synapses and continuous neurotransmitter, repeated neurotransmitter in order to reach the threshold for

04:41 action potential generation. Uh inhibition is by Gaba and binding of Gabba gabba

04:50 channels or cause an influx of fluoride I. P. S.

04:55 M. I. P. P. S. A single synapses

04:58 also approximately 0.5 million volts of hyper . I'm gonna tropic courses. Um

05:05 tropic signaling. I am a tropic when the wagon molecule aceto Colin agonist

05:14 step receptor and that receptor is a and metabolic tropic is when that receptor

05:21 not a channel but it has been to ju protean and it can affect

05:25 ionic channels or through membrane attached or numbering attached secondary messenger cascades inside the

05:34 . You will be responsible for acetylcholine . Remember when the seal Colin Colin

05:41 together Kohli Macedo transfers there's a ch till Colin is loaded up in the

05:48 released in the CMS. You have on a tropical single column the subjects

05:53 metabolic tropical single color receptors. So will be different. The function is

05:59 and this is different from the skeletal and this is different from the cardiac

06:03 in particular in the skeletal muscle. only have nicotine in K.

06:07 H. So it's only an excited synopsis and in the cns synopsis obviously

06:13 have glutamate synopsis which are excited gabble which inhibitor but a ch through nicotine

06:20 acetylcholine receptors will cause deep polarization and mascara nick or metal tropic acetylcholine receptors

06:28 cause hyper polarization in the same Once a seal Colin is released gets

06:33 down by acidic all necessary to see castle Colin, gets transported back in

06:38 and chatted back into pseudo code. we discussed that medications for Alzheimer's specifically

06:43 sudoku Lunesta races but blocking the breakdown acetylcholine master is a pseudo Colin by

06:51 um that's a local investor race. is an increase in the single Colin

06:56 . And so we discussed that for medication this is a system neurotransmitter system

07:02 is impaired early on in the court to a simple coding system.

07:09 so organophosphates will also do the same if you're this is the nicotine Nicholas

07:16 they have their own agonist nicotine and and they have their own antagonist karate

07:20 antwerpen. Let me check the questions quick if I can open that,

07:31 not letting me, So getting back the second we reviewed that the same

07:35 of principles exists for cattle colony. so we reviewed that uh dopa and

07:42 and then later norepinephrine and epinephrine come tyrosine. Um And we discussed in

07:48 detail in europe and africa actually and between europe and africa uh and came

07:57 and talked about amino acid neuro transmission how all of the cells that are

08:02 cells will contain britannicus and deeper box . And if you do carb oxalate

08:08 you take the C. O. . Group, this is Citigroup away

08:12 basically from glutamate produced Gabba. So one enzymatic reaction away major excitatory cns

08:19 into major inhibitory neurotransmitter. We talked about serotonin and how antidepressant medications and

08:30 medications can control. Also the re of these molecules not just a breakdown

08:35 the synaptic club but also the re of these molecules and how each one

08:40 these neurotransmitter systems, serotonin or cata means and aceto Colin. They're involved

08:46 different functions, different moods, sleep learning control and so on.

08:52 then we talked about in the For under cannabinoids. We discussed that

08:56 is two major under cannabinoids and and a tour of the two Roky donnelly

09:01 glycerol and with the polarization, significant polarization in both inhibitor and excitatory synopsis

09:08 can have increased production enzymatic synthesis of with the influx of calcium and then

09:15 cannabinoids are not stored in the Like all of these southern new york

09:19 were just discussing. Instead they've used through plasma membrane and retrograde fashion.

09:25 target CB one receptors that are located optically and these are g coupled

09:30 So this metal tropic CB one receptors actually regulate calcium channels that will close

09:36 calcium channels and regulate the release of and inhibitory neurotransmitters. So the cannabinoids

09:43 this negative feedback loop the pre synaptic and through a little bit tropic

09:49 control the excitatory glutamate and inhibited the of these balancing excitation and inhibition in

09:56 brain and delta nine THC. A nine tetrahydrocannabinol also actually receive you on

10:03 primarily in the brain. Although there also another subtype of receptors called CB

10:08 . Cannabinoid receptor two in the brain expressed in buia dominated more in the

10:14 and the spleen organs that are associated immune function and immune response interrogates signaling

10:22 the release of neurotransmitter from pre synaptic synaptic retrograde signaling is that neurotransmitter traveling

10:28 post synaptic side and binding to pre receptors. This is also true for

10:33 gasses nitrous oxide and carbon monoxide that in the same fashion. They're also

10:39 soluble not stored in vesicles and have pre synaptic matters oxide carbon monoxide target

10:47 to identify the cells. We use techniques in university chemistry consider hybridization and

10:54 of neurotransmitters as well as another technique we discussed that was. And caging

11:01 the neurotransmitters in the neurotransmitter mimic re just shown here of course. Now

11:09 spatial summation, neurons can have spatial . So several synopsis active at the

11:15 time will cement that signal. And signal from $0.5 million 1.5 million

11:23 If you have 40 50 active excited synopsis, it can reach Now the

11:28 can become large enough to reach minus which is the threshold for action potential

11:33 . If you do temporal summation which a high frequency discharge of the same

11:38 potential pilot spike. Again you also a much larger mps B but doesn't

11:45 the same altitude as does with the summation. That's because there's a slight

11:50 if you're activating the same synapse and there's time delay here that allows for

11:56 cps be to start re polarizing rather immediate response From spatially cemented three synopsis

12:03 are activated at the same time and in axons that propagate this action potential

12:10 reproduce it in the salted story conduction each note of Ron beer that there

12:16 a break out of this action potential is the same uplifted at the acts

12:20 initial segment. Ah And that acts terminal And the synapse that's not the

12:29 with inverted cables. But the good is not Meilen eight, it's just

12:34 fully insulated. So that means the is going to escape. And so

12:38 talked about this Lamb. The value the length constant length constant is essentially

12:46 you inject the current which is your the zero value here, injection 100%

12:55 . And then you place electrodes a list and the cable and measure how

13:00 this current decay over distance. And does this current over distance reach 37%

13:07 its maximum. That by definition is voltage. Okay value. The λ

13:18 λ stands for the length constant. how far along this dendrite the signal

13:26 going to travel before it reaches 37% is the length constant. So if

13:33 some reason you have a lot of open and if you haven't done really

13:38 that has very high densities of this lambda maybe Shorter, reaching 37%

13:47 here. But if you have a length constant, that means that signal

13:52 its maximum value will travel a longer here before it reaches its 37% value

14:00 video. So this is synaptic And then for shunting and for inhibitory

14:07 if you have excitatory synapse, it's enough. $0.5 million. $40 million

14:12 may not be enough because you have ambition. If there's no inhibition,

14:16 have excitation and you record from the most of that or part of that

14:23 from that synapses going to reach the . But if you activate inhibition along

14:30 way then you need to have a more excitation. Because if you activate

14:34 not only hyper polarizes the cells but also shuts the currents out of this

14:40 cable and by shunting the currents out the level of the soma and

14:47 Get no deep polarization, No change all. So modulation when we talk

14:55 modulation we talk of course about the protein coupled cascades that are through dental

15:02 potentially cycling KMP protein kindnesses. But come back to the different diagram when

15:07 talk about this again, these are neurotransmitter systems that we discussed when we

15:12 about fast neural transmission. Glutamate and . Of course they have. I

15:18 tropic and metabolic tropic receptors but signaling ion a tropic receptors as fast acetylcholine

15:24 . I wanna tropic and metal tropic receptors but serotonin and catalonians, they

15:32 only through medical tropic signaling and so is different because they are also expressed

15:39 throughout the brain as opposed to the acid neurotransmitters. This is again you're

15:45 pharmacology of aceto colon and the colon the metal but tropic side when you

15:51 a single colon was currently concept. you actually open potassium channel. So

15:57 you activate nicotine receptor, sodium comes and d polarizes the cell. When

16:03 activate metabolic tropic must koranic receptor you this to protein couple protein reaction that

16:11 opens potassium channel potassium leaving will hyper . The song luna made is very

16:20 important to realize that leah is all glutamate signaling and glutamate receptors. Again

16:26 have that ion a tropic and metabolic little interceptors gotta Colombians movement,

16:34 attention and visceral function dopamine. So disorder would be associated with Parkinson's

16:41 attention, visceral function, adrenaline of brain, mood control serotonin also

16:49 So they have overlapping functions as neurotransmitters . But you can see that they

16:55 sub serve. They're kind of a functions in the brain. For the

17:03 . What we looked at is this pull system was classical push pull system

17:08 two metal tropic receptors if you have seat locally and you have nicotine acetylcholine

17:15 acting in opposite way too meta tropic , acetylcholine receptor Then here you have

17:25 subtypes of literal tropic receptors. One beta receptor. Another one is alpha

17:31 receptor in or benefit from binding to receptor stimulates the production of cycle game

17:37 through a dental sightly stimulation and stimulates production of protein kinase assay and putting

17:44 . As for late channels and can channels and keep them open and in

17:50 the same molecule norepinephrine can activate alfa after causing an inhibition of the general

17:58 and decrease in cycling campaign and decrease protein kindness production. So you have

18:04 one is pushing production of something like and protein kind say another one is

18:10 away from producing more of this. systems that we discussed like norepinephrine or

18:17 or even other systems. And here have a single Colin system here that

18:21 discussed some greater life two cooling system see in green. These are the

18:28 in the cns where you will find so moe's that produces silk Colin and

18:36 else. So if you look at example so this is the magna cellular

18:43 forebrain produces acetylcholine and particular pawn teen the latter and also take mental nuclei

18:50 acetylcholine. What does that mean? acetylcholine axons or a seal Colin is

18:57 going to be found in these two . No, because this diagram illustrates

19:04 better. Just like 40 goal in same as the case for snore and

19:10 the same as the case for certain they have very specific nuclei in the

19:14 that express these molecules. So the famous of these cells that produce is

19:20 calling the producer up enough and the Tony and they live in these very

19:26 areas in the brain stem. But projections out of these nuclear the

19:31 The axons have these projections are So of these massive accidents have come out

19:36 project everywhere. Sub cortical e new and to serve the element into the

19:42 cord. That's where they referred to modular Torrey systems to because they specifically

19:50 synthesizing these nuclei the activity program coupled and glutamate and Gaba. They mean

20:00 neurotransmitters. Classical amino acid neurotransmitters that discussed. They will be expressed all

20:07 . You will find cells that are of litter, mate and hippocampus and

20:10 cortex full of gaba in hippocampus and cortex cerebellum and so on and so

20:17 . So that's a big distinction and between these neurotransmitter systems. So just

20:22 remind you that this process is referred as deep polarization induced suppression of

20:28 This process of under cannabinoid signaling where polarization. If you have a lot

20:33 deep polarization, what other cannabinoids do they suppress the release of neurotransmitter.

20:40 if it's deep polarization and release a neurotransmitter, it will be inhibition.

20:48 polarization induced suppression of an ambition. it's goalabama Tajik will be deep polarization

20:54 suppression of excitation or dse amino acids . Again, they will have their

21:02 transporters for glue to glue. Dramaturgical pharmacology have glutamate that will buy into

21:09 subtypes of receptors that are distinguished based their chemical agonists and antagonists tampon and

21:16 and kind. Um they also have pharmacology so they're bound by different agonists

21:24 blocked by different antagonists that different kinetics glutamate is released it will immediately open

21:31 channels sodium flux uh flux, skin the initial deep polarization And only when

21:39 block is alleviated through deep polarization than channels will open. Them cause a

21:44 influx of sodium and calcium. The of opening how fast or slow ample

21:51 responsible for the early PSP component in for the late selectivity. All of

21:58 NBA channels are permeable to sodium calcium potassium and only some I'm for channels

22:05 permeable to calcium And conductance conductance perspective India channels are much larger conductors.

22:13 PICO seamans they also have their own antagonists and ample key name is blocked

22:18 seeing Q. X. And an 80 s. After some blocked by

22:23 PV. Because in the areas after to detect glutamate. It also actually

22:29 a glycerine as a co factor to function and it has to have a

22:36 polarization person optically. So it has have the pre synaptic component, the

22:40 , not the deep polarization because of is referred to as coincident sector.

22:45 coincidentally detective chris an african possible app and it's not to be confused that

22:50 receptor is a metal with tropic with interceptor because an M. D.

22:53 receptor is just blocked by magnesium. is not do protean couple. So

22:59 India is responsible for the late portion the PSP and has a slower

23:03 And you can see that there's many substances uh such as PCP and even

23:09 that has binding sites on an D. A receptor. In this

23:14 we discuss that if you use a clamp and you record currents. Glutamate

23:19 currents and you block ampara receptors. you see is a normal physiological $1.2

23:27 magnesium solution of minus 60 million volts barely see any opening of the

23:32 You have to de polarize the number potential to -30 to start seeing the

23:37 of the channels. zero new It's a reversal for an M.

23:42 . A receptor. It's an equilibrium for an M. D.

23:45 Receptor positive 30 you can see more current. So it's rectifying awkwardly produces

23:52 and prefers to conduct current awkwardly. this is non physiological really because most

23:57 the cells will live in this dynamic of -80 -92 -30 mil levels in

24:06 conditions. Now if you remove magnesium the solution and you use the same

24:12 clamp and you release glutamate and you ample block and you're recording an MD

24:17 , you will see the opening of NBA channels and this proves that if

24:21 remove magnesium blog eliminate will activate an channel. So in the absence of

24:27 or decrease of magnesium and NBA channels going to be a lot more responsive

24:32 glutamate. They're going to be open zero magnesium condition can cause massive hyper

24:39 and the brains leading to seizures Apple apps. Too much excitation,

24:43 much glutamate causing roommate toxicity potential. two, I'd pause that we discussed

24:51 for the fast Tampa early component and level and NBA component. So if

24:58 voltage clamp minus Sadie and you stimulate intimate with this line is and then

25:05 take a measurement of how much current is minus 80. For the early

25:11 you will see that emperor receptors show have a linear I. V.

25:17 . Um and the reversal at zero vault. And if you measure this

25:23 current and the peak of late you will see that at -80 million

25:27 . This would be the circles here are filled circles. The filled circles

25:32 showing that at -80 -6070. You have much of the current compared to

25:38 Ham put -80 -60 and so Only at about minus 40 or so

25:45 India current becomes significant. It's non versus zero in on the walls and

25:51 is rectifying in this outward direction. course the positive charge flow in the

25:58 direction. So if you use an , a current blocker which is a

26:04 and it shouldn't. The fact that component, what you do is you

26:08 an early measurement and one of these early component with a P.

26:14 In it and early component without a in it. It doesn't change anything

26:18 the early component. This a PV a specific block of an NBA

26:23 And if you measure late current in presence of a PV which will see

26:27 these open circles and these open circles near flat line here telling you that

26:34 is no only current left because you it and there is no more current

26:41 you would see. And so the current the NMDA currents of the PSB

26:46 illustrated here in blue collar and this the blue current that would be blocked

26:52 the presence of a PV and would this open circle plots. I hope

26:57 explained a few questions that were there . This is a interesting talk about

27:05 Q. R calcium. Yes for , arginine calcium, no single amino

27:12 substitution can influence whether the sample channel permeable to calcium at early stages.

27:19 an M. D. A receptor expressed or what you call a silent

27:22 and then there's specific subunit shifts in . D. A receptor is is

27:27 the development or to do any of signaling in India receptors in their silence

27:34 absence because nothing is going to dip glass remembering in the absence of ampara

27:39 only an NBA receptors that are affected at the very early age and then

27:44 down for receptors come into play. is of course changes with age and

27:50 , ample receptors can move in and of the synapses in the fast way

27:54 significant plasticity. LDP s test for term plasticity that is mediated by the

28:00 GIC and envy and Amber's transmission for but tropical intimate we discussed. This

28:06 really important that way that if you metal properly receptors you convert P.

28:12 . P. Two through Prospal ibc membrane bond. So literal which can

28:19 the protein kinase C. And the of this pathway into production of the

28:24 triphosphate and activation of the I. . Three receptor on the smooth and

28:30 , particularly inducing an inter cellular calcium for calcium is not only an ion

28:36 also a secondary messenger. Gaba ergic . Gaba binding Gaba a receptor in

28:45 will cause the influx of chloride and or hyper polarization dampening of activity in

28:52 brain. So activation of Gava increases tradition or dampens activity in the

28:58 It's also aside for ethanol, benzodiazepine barbiturate nurse. Terror binding Gaba A

29:05 Gaba receptors. Gaba a receptors uh you bind Gabba to them, chloride

29:13 is gotta be receptors. They are through g protein complex to calcium.

29:19 can block calcium influx and potassium channels they can open potassium channels and cause

29:27 influx. So we discussed this important here and this is just in general

29:35 everything together. You can have a synapse and if you have significant influx

29:40 calcium you can activate calcium kinds tune Gaba b receptors are located both.

29:49 optically and passing optically. So gabby Prison optically will block calcium influx and

29:56 neurotransmitter release is simulated in a way The CB one receptor function. And

30:03 ethically Gaba receptors can open potassium channels cause hyper polarization. So Gabba

30:12 if this Gaba synapses are located here synapses through Gaba receptor, a receptor

30:19 will cause influx of chloride causing the I PSP inhibitory synaptic potential and the

30:26 hyper polarization through opening of the potassium through the gabba. Be metaphor tropic

30:33 and prison optically if this ambient gaba over here it can block further gabble

30:40 . So you have an auto receptor and if you have a lot of

30:44 that spills over into an adjacent excitatory , it can also control the release

30:49 glutamate by activated pre synaptic gaba receptors the grid. Um antarctic synopsis.

30:57 So you can see again that this intricate interactions here between Gaba a baby

31:06 , potassium calcium channels in an D. A. Receptor is this

31:09 a great questions for labeling diagram or for the exam. This is an

31:17 again where if you stimulate synopsis that excited to input. So this is

31:21 stimulus you will first produce E. . S. P. And if

31:25 synopsis are flying to surrounded or innovated inhibitory synapses boom. Gaba A will

31:32 the C. P. S. . Causing an influx of chloride trying

31:36 drive the number of potential to the potential fluoride which is 1 70 million

31:42 followed by the activation of the Gaba receptor and opening of the potassium channel

31:47 the flux of the potassium trying to the potassium at Louisville potential of -19

31:53 walls to grab a beer uh through activation and opening of the potassium

31:59 And if you if you block Gaba receptor antagonist is by curriculum. If

32:06 block this gabba a response and you in one and two it's exact same

32:14 . But you can see that if have inhibition excitation is followed by inhibition

32:19 of controls and checks excitation and And if you don't if you block

32:26 with Baekje column you can see this excitatory de polarizing plateau potential that you

32:32 produce themselves. So a little bit the structure of the G protein coupled

32:39 is seven trans member and spanning alpha and a variety of different mineral tropic

32:47 signaling from Seattle Colleen, Gaba, , dopamine, norepinephrine and couple of

32:54 at peace at peace. Not only the energy molecule and also as a

32:58 and receptors. And we discussed also caffeine as two dentists and recep recep

33:07 Yeah there were dentists and receptors as . Uh This is transmitted gated channel

33:15 . So of course it's different from G protein coupled structure here you have

33:22 little cold in receptor in particular as sub units. Each one of these

33:28 four trans member incitement someone threw them what is notable here is different combinations

33:35 these subunits that cause a variety of of gobble and gobble B receptors and

33:41 of the interesting things is nicotine nick critical stuff. The afternoon nicotine

33:46 agonist carrera entre pena's antagonists um you to know I'm an M.

33:52 A. Of course afternoon the Gabba D. And you should know by

33:56 is the antagonist of Gaba a alpha sorry A TPM dennison receptors, a

34:05 dennison is an agonist will discuss that TPS and agonist agonist for different type

34:10 denison receptor called P two X receptor it's still in the dentist and receptor

34:17 they 80 p. stands for a and triphosphate. And there you have

34:24 as an antagonist for denison. So have these things that are dennison is

34:33 , what it does is uh increases signaling and a dentist and dampens glutamate

34:40 . So in the evening time of levels go up and dampen glutamate release

34:46 brain activity quieted down and let inhibition more active and caffeine does the opposite

34:55 increases gonna make released through a dentist receptors through G protein coupled system.

35:01 is the amplification that you can And also different divergence convergence redundancy parallel

35:08 that you would see in this neurochemical and after our prolonged discussions in your

35:16 and you already had a quiz on there will be more questions on the

35:22 and there's a lot of good labeling that is going to come from the

35:27 . And as I said, I'm going to do necessarily a review of

35:31 CMS because we just finished talking about in the last couple of days.

35:36 I would be happy to take any you may have. And other than

35:42 , I'm gonna leave it here with recording today. Good luck on your

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