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BIOL 4315 Neuroscience Tue Th 4-5.30pm - NEURO Lecture 10 Neurotransmission 2
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00:01 This is lecture 10 of Neuroscience and second lecture on neurotransmission. And when
00:08 talk about neural transmission, we talked these different process of amino acid neurotransmitter
00:16 amine peptide. The difference is between release synthesis of neurotransmitters versus peptides.
00:26 non classical neurotransmitters such as adenosine and TP uh also lipid soluble gas ll
00:37 and endocannabinoid. The slide compared and the differences between neurotransmitter and secret granule
00:47 neuropeptide synthesis and release. Also the that they can be co expressed at
00:52 synaptic exon terminals and core releases. thus, exocytosis as we already spoke
01:00 requires that the action potential that gets at the axon initial. Uh the
01:07 hill out here and gets regenerated in not to run beer that once it
01:12 exon terminal, it's the same So you first of all have in
01:16 exon terminal depolarization because of the action and that depolarization and external terminal open
01:25 CALS. So, and the axon and at the nodes of Ron
01:32 you have high densities of voltage gated channels and potassium channels that are necessary
01:37 produce and reproduce the action potential with node of Ron beer, you'll also
01:42 voltage gated sodium and potassium channels at external terminals. But in addition of
01:48 terminals, you also have pretty robust of pre synoptic, we call them
01:54 gated calcium channels. And so when arrives at the exon terminal, it
01:59 local voltage gated calcium channels, influx calcium through these channels will promote the
02:06 of this vesicular Nero in complex with membrane t smear complex. The protein
02:15 complex interactions will bring the membrane of vesicle to the membrane of the neuron
02:21 cause a fusion exocytosis that followed by . So, the vesicle gets recycled
02:29 into the prey terminal. The neurotransmitters will bind to po synoptic receptors and
02:35 either get broken down here. Uh as acetylcholine by acetylcholinesterase or it will
02:42 reimported back, reimported back into the terminals with the transporters. So,
02:52 uh synopsis will have glutamate transporters that bring them back into neurons. And
02:57 will have glutamate transporters and we vesicles load them up back into the
03:01 Gabba synopsis will have Gabba transporters. synopsis will have choline trans support us
03:08 , coding back into the presyn But it's the same kind of a
03:13 and the same uh similar way in these molecules gets released and then recycled
03:20 into the pre synoptic terminals. So image illustrates first of all on the
03:27 , the electron microscopy, it's called electro photo micrograph of uh uh essentially
03:38 photograph and what it shows it shows presumed calcium channels and you can see
03:43 little buttons and they align all along is the active zone, the presci
03:49 zone. And so this is the channels when neuron is not being stimulated
03:56 when neuron is being stimulated, this still those buttons are calcium channels.
04:01 now you're seeing these craters and you're at the presynaptic neuron. And what
04:07 craters are is that these craters is fusion of the vesicle, the vesicle
04:12 fusing and it's releasing its content into synapse which you are facing.
04:17 you are now on the postsynaptic side this presynaptic term. And uh as
04:24 spoke from the very beginning of this , we always wanted to understand different
04:31 of neurons that are present in the . And our understanding of different subtypes
04:35 neurons stemmed originally from understanding the morphology these cells. So how different they
04:42 like and where they located it, also talked about specific markers. So
04:48 molecular profiles that make these neurons subset neurons a different subtype, which is
04:54 a subset of neurons which is a subtype of cells. And uh with
05:01 advent of fast cameras and fast microscopy became increasingly more interested in the functions
05:10 tracking the functions of these neurons. not just using electrophysiology but using,
05:17 imaging techniques with electrophysiology, you're still limited. If you're doing a single
05:24 recording or what we call a field field potential recording, you're still limited
05:31 how many probes you can place underneath microscope. So if you're patching cells
05:36 whole cell patch clamp recordings, you be amazing and you may patch four
05:43 at the same time. And that that in a single experiment, you
05:46 visualize activity in in four cells. uh uh to record activity in poor
05:54 . Electrophysiological activity. Imaging allows you visualize multiple different neurons, multiple different
06:02 . And uh since the seventies or , neuroscientists have been able to develop
06:09 imaging techniques. One of the most techniques for studying function of neurons.
06:16 when you study morphology, a molecular , molecular profile of cell markers may
06:22 the function or of these cells or expression of different molecules. And that
06:29 you profile the molecular profiles, but become increasingly more interested in tracking individual
06:37 . So, calcium imaging is a common way to correlate electrophysiological activity or
06:44 in neurons with increased concentrations in Uh So this is an example of
06:53 sensitive dye and these experiments where uh of these experiments, this one that
06:58 shown was performed by Rodolfo Lina's probably one of the most famous South
07:03 American neuroscientists. And what Rodolfo Li showed is that here, what you're
07:10 at, you're looking here at the of calcium. So it's almost like
07:14 huge map of calcium concentration. So means where there, where there is
07:18 red, that means it's the highest of the calcium and where there's a
07:23 , it's low concentration of the you're looking in particular intracellular calcium
07:29 So remember there's a lot more calcium the outside of the South than there
07:34 on the inside. So this calcium going through Russia inside the South.
07:40 , what is evident here is that neuron is not stimulated, like in
07:44 electron micrograph here, you have these clearly spatially defined peaks if they present
07:51 spatially confined micro concentrations of calcium that obviously located very closely to the vesicles
08:00 the active cells during the stimulation. can see that there's massive influx of
08:07 inside the cell, but you also that spatial specificity. So there's a
08:11 of calcium prey ical and the calcium . Cynical is now going to interact
08:16 the protein complex on the decibel. is calcium sensitive diet. And you're
08:21 at a single cell here, you're really at a single synapses. So
08:25 have a resolution with these island sensitive and the speeds to visualize the release
08:31 neurotransmitters basically or influx of calcium. you have the resolution to do it
08:37 a level of a single synapse. calcium sensitive diet and calcium sensitive
08:43 that means whenever there's increase in it's pretty well correlated with increase in
08:49 or depolarization in neurons. There are sensitive diets, there are potassium sensitive
08:57 . So there are ion sensitive dyes will basically just like you see changes
09:02 calcium levels. We call them spatial patterns because these patterns are in space
09:09 they happen over time before stimulation. follow legal spatial temporal patterns of calcium
09:18 . You can have spatial temporal patterns sodium fluxus. And there are also
09:22 sensitive dyes that instead of tracking the ion of calcium or sodium potassium will
09:30 correlated with the membrane potential changes with depolarizations of hyper polarization. Those dyes
09:37 be applied on the tissue or they be genetically encoded. So you have
09:44 , genetically encoded calcium indicators, which that they already contain a marker for
09:53 inside the cell. And when calcium go up, you can image that
09:58 and you genetically express it. Advantage genetically expressed dyes such as genetically expressed
10:05 sensitive or genetically expressed voltage uh sensitive is that you can drive into specific
10:13 of the brain and with specific you can drive them potentially to be
10:18 within specific subsets of neurons in the sub type of nerves. I only
10:23 to express calcium, let's say only the excited or cells in the hippocampus
10:30 nowhere else. And that's what you do with genetically expressed uh voltage indicators
10:37 JVI. And um remember when we the structure of the voltage gated sodium
10:45 . We said that S four is voltage sensing subunit and a lot of
10:50 dyes and especially the uh uh the dyes that you apply, not
10:56 they penetrate throughout the membrane, but ones that you genetically express, they're
11:02 be targeting those voltage sensing domains. it will be targeting that you attach
11:10 indicator onto a voltage sensor domain and gated sodium channel. That would be
11:16 four transmembrane segment. So, calcium necessary. So you have calcium influx
11:25 exocytosis. It there is a synaptic . It's sort of a calcium uh
11:31 protein. It's a whole protein but one of them is synaptic Tagment
11:36 detects calcium and it detects calcium. allows for the fusion of the v
11:40 vesicular snare with A T snare. have the confirmational change in the proteins
11:46 are activated. The vesicle mene incorporated the presynaptic membrane neurotransmitter is released and
11:54 vesicle is unbound and recovered via the . So what's interesting in the
12:03 And that doesn't happen in the We already talked about how neuromuscular junction
12:08 has an abundance of vasa and so vesicles that get released. And you
12:14 get this potential, which is massive large in amplitude always generates an actual
12:20 of the muscle. When we talk how in CNS, you can have
12:23 smaller boin api potentials because you all any potentially one vesicle cause very small
12:31 by synoptic with the PSP. And addition to that, in some
12:36 you don't even get a full So these uh neurotransmitter vesicles are docked
12:42 primed for release, they're very close the membranes already, the protein complexes
12:49 influx of calcium. Sometimes there's a fusion where the pore opens only partially
12:55 just a little release of neurotransmitter and returns into this position where it can
13:00 primed again, dark and primed So this is referred to as kiss
13:05 run. So the vesicle comes, gives a little puck to the membrane
13:11 a little bit of neurotransmitter but then away. It doesn't commit to the
13:15 release, so to speak. And other instances of the actual potential is
13:21 properly. Calcium and flux is also enough. You have full fusion release
13:27 neurotransmitter. The endocytosis happens to have Claritin coding classics that have been
13:34 They get coated by Claritin, they acidified with a high proton gradient in
13:40 end with the help of A TP then cot transporters. Uh this proton
13:46 will be driving in partial the You have transported that neurotransmitter that prepares
13:53 vesicle the to repeat the whole In some instances, when vesicles get
13:59 up or too used up, they taken back into the early endo home
14:04 they get reprocessed into the new vesicle then placed again into the cycle of
14:10 followed by endocytosis. So we talked how you have excitatory glutamate and inhibited
14:19 and you will keep learning more and about the systems. Uh The next
14:23 is going to be pretty much dedicated glutamate and Gaba signaling. The glutamate
14:28 will cause influx of sodium will cause of cop potential Gaba release and Gaba
14:36 to these lien gated channels will cause of fluoride negative charge, flexible inside
14:41 cell will cause this hyper polarization in form of IP sp. So these
14:47 the major dominant amino acid neurotransmitters. is the major excitatory Gaba is the
14:54 inhibitor neurotransmitter in the seal nuts. these are transmitter gated channels because glutamate
15:00 to bind to this receptor in order open up the channel Gaba has to
15:05 to this receptor in order to open its channel. OK. So they
15:09 receptor channels. So as we talked in these uh neuromuscular junctions, we
15:17 this massive potential and it doesn't mean this potential will always be 40
15:23 It can be 50 millivolts, it be 70 millivolts. But the interesting
15:28 about potential activation in neuromuscular junction is we always have a delta of 40
15:35 millivolts about 45 to about 55. that's always significant enough to drive the
15:41 to produce an action deduction. This the threshold for action production.
15:45 Epp always crosses this threshold However, talked about how in central synapsis you
15:53 have very small responses. And uh we also understand is that there is
16:01 certain number of neurotransmitters inside the So that NASA will contain what we
16:13 to as squatter or quantum quantum amount that neurotransmitter chemical. And it actually
16:23 between 6000 individual molecules. So, , well, that, that's
16:28 That's really standardized quantum unit. it is variation in this amount 2000
16:36 4000, let's say a P Cyl molecules in the, in the
16:41 but it's not between two and 20,000 . So there is some approximate number
16:48 about the same between the 6000 So it's almost double in some
16:55 Uh And in neurons, what we about in neurons, we get these
17:00 small EPSP. So if you have synapse and you stimulate the synapse and
17:06 released a single vesicle here, you're get a very small EPSP and you
17:14 record, you can actually record spontaneous . That's what how it's quite often
17:20 . So, electrophysiological spontaneous activity will you, I drew that in the
17:26 before very small fluctuations like the one just showed you sometimes it'll be
17:31 sometimes it will be hyper polarizing, or large or very large until they
17:38 the threshold. And so you have EP SPS and you have these IP
17:43 . And if you have depolarization and of single neurotransmitter vesicle. You can
17:49 what we call mini, mini miniature potentials. Uh And in these
17:55 potentials, you basically will find the depolarization that you'll always find. And
18:02 they end up being approximately 0.5 millivolts , in size and then you'll find
18:10 of them that will be, let's 1.5 millivolt in size. And what
18:16 means is that if you release one and one synapse, you activate this
18:24 . And if you find something that one millivolt, that means you're now
18:29 two vesicles, two synopsis three times gonna be 1.5 millivolts. And so
18:35 the cell in the C MS to the threshold for action potential, you
18:40 have to simultaneously activate terms of the synopsis or increase the vesicular release or
18:48 repetitive trains of action potentials in order that this epsp can reach the threshold
18:55 like lay potential does so easily at neuromuscular junction. So C MS Synopsis
19:02 not as reliable as the neuromuscular They're not as strong in depolarizations,
19:09 as reliable. It be partial full fusion and small potentials. And
19:17 junction is what we call high fidelity . That means that potential always results
19:25 a twitch of a muscle and you get potential when you have a release
19:31 a single neuromuscular junction. So we used the acetylcholine example in the past
19:40 we'll continue using acetylcholine example. We at it in neuromuscular junction. And
19:45 was very easy in the neuromuscular junction there was only one sub type of
19:50 acetylcholine receptor and that was nicotinic acetylcholine . So, neuromuscular junction only has
19:58 acetylcholine receptors and those are ionotropic. this is the acetyl colony resaca that
20:05 a channel. Remember, neuromuscular junction of a PSE colon receptors caused the
20:11 , initial depolarization in the muscle before opened up voltage gated sodium channels and
20:17 the muscular action potential. So now the CNS, the story is different
20:24 the CNS, we actually have receptor and we also have metabotropic or muscarinic
20:30 coma receptors. They're abbreviated as M RS. So, nicotinic versus muscarinic
20:41 the suit of Colleen it is in synapse. First of all, on
20:46 street and not the terminal, it synthesized with Chat coen aid transferase.
20:52 makes cline a co a chat synthesizes as ach transporter uploads it into the
21:01 vesicle fuses releases ach ach binds to receptor, either the trophic or metabotropic
21:10 these chemicals are released and they bond the receptors, they don't stay there
21:14 forever. They induce a confirmational they'll open a channel and they dissociate
21:20 they float away from those receptors, don't have a covalent bond to the
21:26 that will hold them on there for . So if it is something that
21:30 the channel, we know it's called . And a lot of them are
21:35 agonists. That means that they bind bind, bind and, and
21:38 If there's a lot more of it in the synapse, it may bind
21:43 to another receptor that hasn't altered its yet. But as it induces this
21:51 of nerves and it's in the acetylcholine gets broken down by acetylcholinesterase.
21:58 it has an enzyme that degrades it the synapse into choline acetic acid.
22:05 choline gets transported back into the presynaptic through cline sodium cot transport. So
22:13 has to be reuptake back. This called reuptake of neurotransmitter. And then
22:19 has to get synthesized and to see colline and then it has to have
22:24 ach transported in the vesicle to load up in the vesicle and repeat the
22:30 cycle. So molecules don't stay in synopsis for long. They do their
22:35 binding to the receptor sac and causing response, either ionotropic or metabotropic G
22:42 coupled response. And then they get back in some instances. Acetylcholine,
22:48 get degraded within the actual synapse. , we're gonna talk uh quite a
22:55 about uh but so I don't talk me as we talk about acetylcholine
23:02 And uh there's a section in your that's called bacteria, spiders,
23:07 And you and people used to be on you, but it's and
23:12 So why are we talking about And how is Botox actually relevant to
23:21 or cholinergic neural transforms? So, everybody has heard of botulinum or
23:31 No. So this is uh canned , like if it's improperly stored,
23:37 it's expired, that's why you don't it expired cans to food. Uh
23:41 drives, uh you have to give uh non expired food uh as a
23:48 . So uh quite often there will bacteria that form inside poorly stored or
23:56 or preserved food. And those bacteria generate boche line of toxins and they're
24:04 . And if you eat bad canned , ingestion of these toxins can be
24:11 actually. Uh And why is And how it works? The mechanisms
24:18 action of toxin is by blocking a release. It targets the snare
24:28 Remember, the snare protein is on vesicle side. And so Botox botulinum
24:36 , there's different variations of it A CBD FG. And that's one of
24:44 toxins. Here are these sharkies, they essentially do is they chew up
24:50 protein complexes and these snare and these complexes and they don't allow for the
24:56 protein complexes to inter right? We to have this protein protein complex interaction
25:02 order to bring the vital and cause . So these guys snip off these
25:09 protein complex interactions and interfere with the release a pseudo code. Now let's
25:21 on online and please forgive me if open things that have commercials. So
25:30 guy and his wife are getting like for years, right? So you
25:35 to repeat these treatments. Sometimes they you champagne when you do that because
25:39 encourages people to go, you and relax a little bit as they
25:43 injected in their, in their But why are we talking about that
25:48 is because it, here it deals wrinkles. So it's Botox for Beauty
25:55 it deals with wrinkles, how it with wrinkles by blocking acetylcholine release.
26:01 do we have wrinkles because we move on our face as we talk,
26:06 we gesture and the more we the more we gesture, the more
26:11 we form around our eyes, cheeks, whatnot, forehead. And
26:18 Botox injections do is they block this release. So like he said,
26:24 , look at me seven days look at me 30 days later and
26:29 has a little bit of those wrinkles because his muscles are not contracting now
26:34 much. And therefore there's not really showing off of those wrinkles. So
26:41 amount of this toxin, they they didn't feed him bad canned
26:46 but they controlled the mouth and the the syringe now is a, is
26:51 , is a beauty treatment. You have to repeat it. So
26:56 , his wife is doing it for . How many times a year?
27:01 don't know, some people do it lot, you know, uh and
27:07 the housewives of whatever, how many these they get a year, you
27:12 . So let's go back and look more commercials. Let's go for Botox
27:20 migraine before treating your chronic migraine, or more headache days a month each
27:33 four hours or more. You're not only one with questions about Botox.
27:38 prevents headaches and don't have chronic migraine they even start with about 10 minutes
27:43 treatment once every three months. Look at this, Doctor Botox.
27:48 look at this. This is now we're talking about the Botox treatment
27:53 migraines and this is the regimen. just missed it right here. 10
27:58 of treatment every three months. So three months, you have to get
28:03 injection. All right, they've I believe, close to 200,000
28:10 This is the FDA food and drug . This is the agency that regulates
28:15 the medications and drugs. Uh They it for migraine migraines. It has
28:21 approved for for a while. What's, what's the, what's the
28:28 of action there? Obviously quite a of drugs. We don't know the
28:33 of action. We know now, example, that we're using Botox.
28:37 it's gonna uh inhibit neurotransmitter release a . But a lot of drugs like
28:44 drugs or, or other medications, don't even know mechanisms of action.
28:50 don't exactly know what type of channel mine or after you don't really need
28:56 know that pharmaceutical companies don't really need know that they would like to know
29:03 everybody else would like to know that scientists would like to know that pharmaceutical
29:08 want to make sure it's safe and . And so if it treats
29:13 it treats cancer and it's safe, get the mechanism of action. You
29:18 , it's a scientist that have to more of that work rather than the
29:22 companies. But, and you, either judge yourself, is that good
29:27 is that bad? The more we to know about what drugs do,
29:32 more mechanisms of action already to deliver drug on the market. A billion
29:36 for you. A drug in 10 of work, the army of
29:41 95% of them fail clinical stage three . That's, that's so if you're
29:48 now tell people that are developing the , you must show me all the
29:53 of action in the brain and then stomach is just swallowing and everywhere.
29:58 know, that's another what, 20 years before you have a,
30:01 drug treatment. So it's something You don't think about a lot.
30:07 , the cell drugs we know very the mechanism of action. How do
30:11 do? They target cox one cox anti inflammatories, you know, all
30:16 that. But others, especially newer . Uh so even Blockbuster things,
30:21 don't know about the big Blockbuster. , is. 0000, Z A
30:29 C A, one C inhibitors. a huge thing. Most of them
30:32 injection, there's a pill and the is doing really well, you
30:37 And so, uh, there are also kind of a trends in what
30:41 pharma follows. Uh, so everybody now on the bag bandwagon of a
30:45 C, you know, losing weight a one C 50 cents looks
30:50 but I don't think he went to gym. So anyways, so now
30:56 have it as medicine and it's FDA . Notice the size of injection just
31:03 a video where a guy Ryan which name was getting injections here also.
31:09 it's similar size of injection except you more on the head, on the
31:14 of the head, you go more the back and it reduces some of
31:19 muscle spasms associated with migraines. And mechanisms of action is not very clear
31:25 we are still trying to figure out migraines come about and we know some
31:29 , how they do the cellular mechanisms it but not in, in complete
31:35 overview of what happens during migrants. therefore, it's not exactly clear exactly
31:41 it works with control of migraines. know, in other words, if
31:45 took the pill cholinesterase uh uh something inhibits uh vesicular release, for
31:53 you know, then and would it the same effect? So there's other
31:59 intermediaries and cellular processes that may be . Now, uh Black widow
32:07 we actually have blue, pretty much that's like poisonous, lives in
32:13 It's rattlesnakes on the, on the coast here and on the marshes,
32:19 have funky wasps, you have We don't have Taiwanese Con for
32:25 It looks like it would be in . Uh but black widow spiders we
32:31 inside, they have venom. So lot of these critters will have
32:36 venoms will have different compositions of These venoms can kill um they can
32:45 other animals. Um We just had very interesting talk in our department about
32:52 wasp that injects its venom into, fly larvae and take over the larvae
33:00 actually grow out of it babies out it, you know, so different
33:05 have different functions evolutionarily but they contain molecules lact toin. In this
33:13 black widow spider, it punctures cells depletes calcium and it can facilitate neurotransmitter
33:21 without calcium. Whoa That's really What's going on. So it's probably
33:29 puncturing holes in the cells, making leaky and somehow even without calcium fluxing
33:37 properly, it still is promoting this neurotransmitter release as facilitating. So,
33:45 stops neurotransmitter release. This Lato toin neurotransmitters. Taiwanese cobra expresses alpha bunger
33:55 toxin. Alpha bunger toxin is targeting ay and poin subject. So you
34:04 the cica release, you can inhibit or promote it. You also have
34:10 receptors that you can target and postsynaptic receptors cause desensitization and causes respiratory muscle
34:22 . So, this is a Taiwanese . I mentioned that already in this
34:27 . Who do you call those Who do you call when you get
34:32 by a cour poison control? Don't 911. They won't know anything.
34:42 nobody ever has to do it but control, they know how to deal
34:46 these kind of things and they'll walk through. If you call 911 nurse
34:51 somebody, they'll be like, we'll come pick you up, you
34:55 , you're two hours away. Wait, dead muscle paralysis. So
35:01 when it comes to people, or you or us, we synthesize
35:07 kind of phosphates which are nerve which are chemical weapons such as sarin
35:13 , for example, um, nerve , uh, are illegal in military
35:23 . But they have been used, been used by terrorist organizations and
35:27 There was a famous Tokyo Metro attack the nineties with the nerve gas.
35:36 , last week, uh, Russians Navalny. Supposedly they killed Navalny.
35:43 don't have a confirmation of that. , but this is not the first
35:48 they tried to kill him. They tried to kill him with nerve gas
35:52 I think it's 2020 I believe. . They put it in his under
35:57 he got on the plane and they managed to rescue him and save him
36:04 pump him out. So this the uh attempt is not clear how he
36:09 . If he was poisoned with nerve , there is an uh theory that
36:13 was punched after a long cold When his heart slowed down, he
36:17 punched to basically drive him into a arrest. So it's not clear.
36:23 then why would anybody put nerve gas the underwear? I'll tell you
36:28 First of all, if you put on somebody's hands or their shirt,
36:34 will affect others. These substances are, are quite penetrative on
36:39 Ok? So if you expose it somebody else or something like that through
36:43 , you know, they could be floating up a little bit because their
36:47 is pretty volatile. Ok? So don't want to do that, you
36:52 to target one person. The other is we talk about how is the
36:57 way in the body to get medications drugs, right? We already talk
37:01 of the things you swallow. And we talk about it goes in the
37:04 system, only a fraction of that goes into the guts. It goes
37:08 the blood, it penetrates blood brain into the brain. And we
37:13 oh, nasal sprays are more You can drive something directly into the
37:17 through nasal sprays. Discuss transdermal. said, oh, if you do
37:21 , you bypass the digestive system, get directly into the blood, the
37:26 goes systemically because distributed, right? of the best ways to distribute things
37:31 through either anal or vaginal suppositories because have very strong blood supply in those
37:38 . And you also bypass digestive right? Because it goes directly from
37:44 areas, it goes directly into the . So that's why they put it
37:48 his underwear. Otherwise, if you to uh eliminate a lot of
37:52 you just release it, release it the air, what it does?
37:57 an irreversible ach E inhibitor. So i irreversibly blocks this. Remember we
38:04 about reversible versus irreversible. So irreversible it and want it if they hang
38:09 it if they bound to ach E bo so you have overabundance of
38:17 you have desensitization too much ach you desensitization of ach with Softwares and uh
38:26 basically you now have a, you a problem, you're leaving this uh
38:34 E you're inhibiting it but you now too much ach. So when we
38:40 about neurons in the brain, we signaling in the brain. But a
38:44 of these things is respiratory failure too obviously you have ach signaling in the
38:51 . So as we discussed, including the diaphragm muscles, uh Periton is
38:57 in insecticide, it's toxic in high . It is also uh targeting uh
39:05 acetylcholine system. And finally, the that are called esterase inhibitors. Most
39:14 the Alzheimer's medications on the market are erse inhibitors or sc nease inhibitors.
39:23 , add this to your rolodex page the Alzheimer's disease. We talked about
39:28 cellular pathology, hallmarks of cellular beta amyloid clocks, Tau Tangles.
39:36 talked about symptomology, memory, things that. And then I said,
39:44 about these chemicals as they're involved in neurological disorders. So in Alzheimer's
39:50 there's going to be an early loss cholinergic neurons. Think about how cholinergic
39:56 are confined to these nuclei that we about. So that's all there
39:59 There's just 23 nuclei that produce these neurons. Ok. So what does
40:08 medication do? This medication increases the of acetylcholine because it blocks acetylcholinesterase.
40:16 there's more acetylcholine and there's no cure Alzheimer's disease. So the only thing
40:22 you can do with Alzheimer's disease is can slow down the progression of the
40:27 . Remember, we talked about how , it starts early days, it
40:31 until it can get severe stages of disease. So all it does,
40:36 slows down the progression of the So let's say if the progression of
40:41 disease, let's say it's 10 years the time you have this disease to
40:47 prediction of the terminal end of your , it's 10 years. So what
40:53 medications do is they prolong and alter progression and then the effect of Alzheimer's
41:00 alters it by 20% or more. 10 plus 20% that's 12 years you
41:10 , so it slows down the hopefully gives you a longer lifespan,
41:16 there's nothing that can cure the There's a new medication that came
41:23 That was all the rave last year slows down the progression. About 30%
41:28 not act with cholinergic mechanisms. Um there's also melanin that targets glutamate receptor
41:38 D A receptor. It's used as medication, but most of the stuff
41:41 on the market to treat Alzheimer's disease block acetyl coma service. Yeah.
41:51 the problem? What if you don't acetyl pill in urine? What is
41:57 drug going to do? Nothing? ? So if these neurons are
42:04 that means that there's not enough acetyl being synthesized. So if you put
42:09 drug that really breaks down that, blocks its breakdown, that's not very
42:18 . So you guys have to think new medications for Alzheimer's. This
42:22 you have to think about what else be done. Why can't we just
42:26 a seal codeine? Ok, I don't know about polling and just
42:32 polling and how about injecting it? about spraying it through the nose?
42:39 guys are gonna have to figure out new medications for Alzheimer's disease.
42:44 all right, let's move neuropharmacology. already are becoming pretty good at
42:50 It's really understanding mechanisms of actions of pharmacological agents, drugs and molecules and
42:56 they interact with the neurotransmitter release, they interact with the receptors where they
43:01 and bind on the receptors. study effects of drugs on nervous system
43:07 just like we have agonists which basically open the channels. We also have
43:16 and that can inhibit neurotransmitter receptors antagonists of opening them or activating them.
43:24 can close the receptor channels or it deactivate the metabotropic cascades of those
43:33 defective neurotransmission, influx of calcium or one of these transporters or breakdown of
43:41 . For example, and the synoptic is associated with neurological and psychiatric or
43:49 mental disorders. Carrara is an antagonist aid Cobe himself. So this is
44:00 the presence of Curare. What happens that unplayed potential becomes very small.
44:07 , Kari will block the action potentials the muscle and botulinum toxin acts how
44:19 toxin prevents the vesicle fusion. So , you can target neuropharmacologically. You
44:25 target vesicle release, you can target this case, vesicle release, you
44:30 target postsynaptic receptors or you can target mechanisms in the synapse to transport them
44:38 synthesize or degrade, there's different So Gaba, for example, will
44:45 Gaba, it's an inhibitory synapse and if it binds to Gaba, a
44:51 , which is an ionotropic Gaba receptor will cause influx of fluoride and will
44:58 IP sp with many pre synoptic terminals contain auto receptors, especially Gaba,
45:06 terminals, auto receptors means that this releases Gaba and there are postsynaptic
45:14 But on this pre synoptic membrane, are Gabba B receptors, these are
45:20 receptors. And if you activate Gaba receptor presyn ically, it will now
45:27 this voltage gated calcium channel and block influx of calcium. Therefore, it's
45:33 to block its own Gabor release. this is like a negative feedback
45:42 You're releasing Gaba, small amounts of will target postsynaptic neurons and cause IP
45:50 fees. And if there is more Gaba being released, that GBA can
45:56 and bind to Gaba, the autore which through G protein coupled cascade will
46:03 calcium and block Gaba release and negative to them. So again, you
46:11 target, if you're looking at If you targeted presynaptic Gava B
46:18 you could interfere with and activated this coupled receptor, you could interfere with
46:25 Gaba release sort of like a safety . And it's very common in in
46:33 inhibitor or transmitter release in particular. when we talk about metabotropic signaling,
46:42 signaling, in particular, uh like , this would be like an example
46:49 muscarinic se boline receptor that will like binance of that receptor. It's not
46:54 channel, instead it's activating G protein it contains different subunits and catalytic subunits
47:01 this Eoin complex and interact with the ion channel. In the case of
47:06 aceto colon interacted with potassium channel also of interacting this is referred to as
47:15 shortcut path instead of interacting through duo couple with other ion channels. It
47:21 activate secondary messenger cascades. It can activate enzymes and secondary messenger cascades inside
47:29 cell. So the secondary messenger cascades influence many other molecules inside the
47:36 including transcription factors, uh and the of the nuclear level synaptic integration.
47:47 , it's the process by which multiple potentials combined within one posy tic neurons
47:54 that a single neuron will be receiving of inputs and it will be receiving
48:00 of excitatory inputs. Blue dots blue , be sorry synopsis and then inhibitory
48:09 orange synopsis. And it can receive of inputs within, let's say 20
48:17 . It's a very short time period it's constantly going to be computing and
48:24 and averaging over those inputs. Integrating information. The SOMA has to integrate
48:29 information has to do it within milliseconds that this neuron can decide it might
48:34 follow us enough to produce an action and communicate that information downstream to the
48:40 networks. So there are strategies by neurons summ made their signals,
48:48 And one of those strategies is spatial in spatial summation. This is a
48:55 axon on the lap here with a action potential that causes a small
49:00 But if this neuron, this dendrite receiving three synopsis and the the activation
49:08 the synopsis is immediate at the same . But across space. So this
49:13 spatial summation, you get much larger in the EPSP. Now you have
49:20 three synoptic potentials together into this much GPS P. In other situations,
49:29 will use a strategy of temporal In that case, it's the same
49:36 , the same axon. But instead sending a single Axion control, it
49:41 send the train of action controls down axon repetitively release neurotransmitter, a few
49:48 release more neurotransmitter, a few milliseconds release more neurotransmitter. And what happens
49:54 then you have a temporal summation or in time. And notice that if
50:00 is a without any summation, this spatial summation and this is temporal
50:11 And what you can see is that get the highest depolarization level, the
50:17 effective way is to do spatial summation temporal summation happens over time. So
50:25 gets released, you generated EPSP but EPSP is rep polarizing second neurotransmitter vesicle
50:33 third release. So there is a here. There's a time delay
50:37 OK. It's temporal summation. But is still a good strategy to increase
50:42 depolarization level. Yeah. Would there a period there or no?
50:47 it would be. And each cell have a different refractory period. So
50:53 . Uh it's a very good Then you'll have a few milliseconds delayed
50:57 typically those action potentials will come interspersed a few milliseconds. It will it
51:03 come at a frequency at which the hill can produce them recover. It
51:07 depend on the speed of the action . Good question. OK. Now
51:14 have another issue to deal with is we talked about action potentials, we
51:20 about nodes of Ranvier in this image at the very beginning, we said
51:26 these nodes of Ranveer and Axon Hillock loaded with voltage gated sodium channels.
51:34 So just keep that in mind and regenerates because it's insulated, it's
51:42 Well, that's not the case with guns. So they're not myelinated.
51:48 Axon is special, Axon gets the gets the myelin dendrites do not.
51:54 so what happens is if you have depolarization, let's say this electrode here
51:59 mimics the synaptic input. But let's you produce a strong depolarization, injected
52:05 current. And this is the site the injection which is essentially do.
52:12 the site of an induction will have or maximum amount of current that you
52:17 generate right here with disperse reporting you'll see this massive depolarization.
52:24 if you stick a second electrode, micrometers away a certain distance away and
52:31 forward along this dendritic cable, which see is that it's only a small
52:37 of that depolarization that travels down the . And the rest of this current
52:43 leaks out because of the lack of insulation. So this is non insulated
52:49 the distance distance which from 100%. o over exponential X lambda, lambda
52:59 the length, constant length constant is distance. How far does this signal
53:08 ? And the length constant measures from and exponential decay to 37%.
53:18 This is the lambda here and the here is the length constant of the
53:26 . So the decay exponential decay from to 37%. And that's the white
53:34 . But different cells will have different constants. Some cells will have really
53:41 length constants and other cells will have lengths. What does that mean?
53:51 means that if it's a long length , that means the signal is going
53:56 be able to far travel much farther . If it's a short length
54:04 that means that the signal is going leak out very quickly and will be
54:09 distance away. OK? Within this decay reaching the 37%. Ok.
54:17 in reality, dendrites are not straight , they have very complex branching.
54:23 so the current is gonna be taking turns and branching, right.
54:31 Many dendrites have voltage gated sodium calcium potassium channels. So there's a strategical
54:37 to have a lot of these voltage channels that will promote the flux of
54:43 over the selma. They can act amplifiers of finn potentials rather than just
54:50 leaking the current. So if you the voltage voltage gated channels, you
54:54 boost and continue the travel of this dendritic sodium channels. And some cells
55:00 carry electrical signals in opposite direction from outward along the dendrite. That's how
55:07 back propagating action potential, the sodium back propagating from the SOMA into the
55:14 or from the Axon into the SOMA into the dendrite. OK. And
55:20 think that I'm gonna leave it here . Uh maybe and a little bit
55:25 today, we'll come back, review couple of these slides and then we're
55:29 jump into, into Glutamate and Java we'll get into details of uh how
55:35 , the neurotransmitter cycle and how gar involved in Glutamate and Java cycling in
55:42 . So see everyone on Thursday. you like
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