VideoPoints

• ••• • •• • ••••• • •
BIOL 4315/6315 Neuroscience (18563/18591) - NEURO Lecture 12 Neurotransmitter Systems II
Help Tour
© Distribution of this video is restricted by its owner
Transcript ×
Auto highlight
Font-size
00:00 risk. So today we will continue about the neurotransmitter systems And this is
00:11 12 of neuroscience. The neurotransmitter systems we saw have several different components that
00:19 synaptic components. Their synaptic components within synaptic cleft. They're also passed inactive
00:26 prison optically you have to have the to synthesize. You have to have
00:31 to transport your transmitters back into south transport them into the vesicles in the
00:39 . You have a releasing machinery. have vesicles that are specific to glutamate
00:45 specific. Done score vesicles peptides. Now you also have boston optic components
00:55 are receptors the boston optic receptors. we discussed that those receptors can be
01:01 a tropic or they can be metal , meaning that if there are no
01:08 then the receptor channels. If their tropic then their receptors that are linked
01:12 g proteins intracellular early that mediate into actions. You get the level of
01:19 number of downstream within the molecular cascades secondary messenger cascades. Some of the
01:26 techniques to then study different components of neurotransmitter system is the immune artistic chemistry
01:33 situ hybridization mimicry of neurotransmitters or synoptic if you may and also caging and
01:43 of neurotransmitters which is the additional information was in your supporting class materials that
01:49 about engaging which allows essentially for very activation of single synopsis using laser microscopy
02:00 all of these techniques can be applied studying the pre synaptic components for studying
02:06 receptors for synaptic receptors are studying degrading such as those who still call industries
02:12 would be found in the synoptic They can give you a bird's eye
02:16 of the whole embryo. If you're at developmental stages can give you a
02:21 eye view of the developing brain structures they change with time. Different markers
02:28 identify different proteins in different components of systems. Also evolve, mature and
02:37 with time and also change and get by different pathologies. Yes.
02:49 In reality, when you study the system and when you study, let's
02:55 any one of the neurotransmitter system you're likely to use multiple staining
03:01 You're likely to use multiple markers So when you hear about double or
03:08 immunities to chemistry immuno fluorescence that means you're using two or three antibodies that
03:14 directed potentially against different parts of a of interest for you such as the
03:21 enzyme and degrading enzyme and there is that receives that quality. We want
03:26 see it all together. And so you would use different fluorescence and different
03:33 markers that will allow you to simultaneously all of the different components of a
03:41 system of interest. These are some the neurotransmitter systems that we've discussed in
03:48 . We will know a lot at end of the sports about guido
03:53 GIC signaling and at the end of lecture about Gabby allergic signaling and Colin
03:59 signal And as you recall glutamate and , the major amino acids, neurotransmitters
04:06 missy locally in is the major I you're a transmitter that you studied in
04:12 detail but we also addressed other molecules as the production of serotonin from trip
04:18 fan or the cata cola mean cascade piracy um to doping me into one
04:26 . Um So you should know certain of that but not all of the
04:30 and synthesizing and degrading enzymes for all the systems apart from the three most
04:36 one. So let's see the cooling you know really well. The synthesis
04:41 acetylcholine with the help of chad gets the vesicles gets released. Austin
04:46 It will buy into nicotine nick, single building receptor channels and binding of
04:51 civil code into these channels will cause influx of sodium and pasta. Matic
04:56 polarization, this negative legacy locally in is also permissible to potassium. So
05:01 sodium rushes in and causes deep The re polarization from this potential will
05:07 from potassium reflux in through the nicotine receptor channel from the inside to the
05:13 of the south still Colin. Can buy into mascara nick. I see
05:18 coding receptors in the cns and some these receptors can be expressed in the
05:23 synopsis really can be expressed in different or they can be expressed in different
05:29 that are located nearby. So the from acetylcholine nicotine receptor is going to
05:35 a change in the number of potential is fairly fast because it will open
05:40 channel or will allow for sodium to The in fact the versatile clothing binding
05:45 middle. The tropic masculinity receptor will you 13 couple protein cascade and downstream
05:53 potassium channel which will take sometimes a delayed response. Okay. And the
06:00 of nicotine receptors influx of sodium which deep polarization and as you will see
06:06 fact that most chronic receptors influx of which is hyper polarization. So they
06:12 of these systems Iona tropic and metal tropic systems, they could be working
06:17 each other either at the level of number and potential or downstream the intracellular
06:23 cascades. And we'll illustrate some of examples. A single clothing in the
06:28 club gets broken by down by cyclical . Growing is transported back to the
06:34 we synthesize goes through the same cycle alzheimer's medications for the most part targeted
06:40 investor race by inhibiting as a vehicle race and prolonging the by availability opposite
06:48 coding. And that remaining synopsis euro you can distinguish between different receptors whether
06:56 nicotine, IQ or mascara, nick . The tropic, formidable tropic nicotine
07:02 an agonist for nicotine, it must from Moscow manicure ari. For
07:07 it is an antagonist and ultra pean an antagonist from estrogenic or something when
07:13 little company and binds to the mosque receptor you have what is called the
07:18 path of initiation. This is called shortcut, partly because the activation of
07:23 . Protium interacts immediately with a nearby and this channel is a potassium
07:29 The shortcut faculty because there is no chemical intermediaries like secondary messengers between the
07:35 protein coupled complex and the target channel is potassium channel. So this gamma
07:42 will have a binding site on the channel and opening of the potassium channel
07:47 cause positive, starts to leave the , leaving the inside of the cell
07:51 negative or hyper polarized. And this began to to to to what I've
07:57 earlier that nicotine nick receptor channels to influx of sodium will dip polarizing
08:04 mascara, nick activation of masculinity, Colin receptor, which is not a
08:10 . The G protein receptor, G coupled receptor activation of the G podium
08:16 open up nearby potassium channels with some , must quranic. If the two
08:20 co express nicotine, it will dip and with some delay activation of masculinity
08:26 the same molecule with some delay will polarized the number of the country.
08:31 why they have actually opposing actions at level of the charge crossing plasma
08:41 Um This is also the system that understand pretty well. In addition to
08:45 Kobe and we understand the glutamate system well and we'll understand the glutamate subtypes
08:50 synaptic receptors right now we're talking about of glutamate and cycling still. But
08:56 be looking later in this lecture and person attic glutamate receptors as well as
09:01 gaba ergic receptors remember is a tripartite . Pre synaptic neuron past synaptic neuron
09:08 leah in glutamate cycling. Glutamate that released. Person optical. It can
09:14 bind to ion to tropical intimate receptors metal tropic with major surface which will
09:19 the subject matter in the next few from now glutamate when it binds do
09:25 receptors, it also gets recycled back optically through the transporters that are neuronal
09:31 and released again. Word gets really taken by glial glutamate transporters. It
09:37 getting broken down and made into glutamine centers and glutamine is given back transported
09:45 neurons and contaminates with the help of and ATP synthesizing to glutamate and re
09:52 into the vesicles. Who is a part in controlling the amount of available
10:01 neurotransmitters. Glia is the astra site is located here because part of this
10:07 from the synoptic club doesn't return to . So as much as this neuron
10:12 like to release more and more glue maybe we are saying no wait a
10:16 let me put it through my cycle is again a slower cycle because you're
10:21 glutamate and glutamine, you're exporting You're importing glutamine, your real synthesizing
10:29 and your imp uploading the vesicles. this is much slower so in a
10:35 glee is concerned with the slower uh and regulation of good and made.
10:43 it plays a major role in how two neurons pre synaptic unfasten optical communicate
10:50 each other and the availability of that demon and neurons Cata cola means.
10:56 talked about tyrosine and l dopa norepinephrine and epinephrine and we talked about
11:04 molecules as being the upstate molecules the the net foreign and north and now
11:12 with adrenaline of the brain uh dopamine well. Uh We discussed this very
11:21 motor functions and if a civil Colin impairment Macedo Colin is common with Alzheimer's
11:29 and pseudo Colin pathways of targeted Alzheimer's pharmaceuticals, then the cata cola means
11:40 pathway and dopamine, for example is in motor control. And so motor
11:50 , central nervous system, neurological motor such as Parkinson's disease which may have
11:56 , certainly truly have spasms that really from four signalling in the Cns.
12:04 is the molecule dopamine that it's linked . And it's a common theme that
12:09 along this pathway the release the degradation the versatile Colin or cata cola means
12:17 the re update in this case the uptake of cata cola means is regulated
12:22 amphetamines like cocaine and what it does blocking the transport. It prolongs the
12:29 availability of this up neurotransmitter op molecule the synoptic left. So the other
12:41 that we discussed also serotonin and we it Trip to fan if you eat
12:48 for thanksgiving or uh is a precursor five Htp and five HTP you can
12:55 of a good mood, good appetite , sleep molecule motivation and learning.
13:04 so that relaxation when you eat big dinner parties from trip to fan not
13:09 from being full as you have a that's now generating serotonin inside inside your
13:17 . And you can see again a from ecological pharmaceutical tactic. Common
13:25 the anxiety medication PROzac, that will the reuptake of serotonin. They d
13:30 is to prolong the mouth or the availability of that molecule in the synoptic
13:38 . And there is by far less that will target the release. But
13:43 neurotransmitters which is which is a whole of study if you want to.
13:49 say instead of prolonging the availability can this serotonin vesicles and the amount of
13:56 may be normal but something is wrong the release machinery. And so how
14:01 you maybe make these vesicles stick better the membranes so that they can spill
14:06 contents into the into the amount that more effectively. Um But all of
14:12 elements along the pathways are definitely targeted should be targeted for pharmaceutical and pharmacological
14:20 manipulations. Now this is an example , we talked about nicotine, IQ
14:27 receptor, it's going to be So what's going to we're going to
14:32 potassium channels going to hyper polarized Now let's look at what can happen
14:39 a lot of these means and a of the um interactions for molecules north
14:46 Afrin more adrenaline serotonin, they all through g protein coupled cascades. And
14:52 then the question as well do they opposing actions? And the answer is
14:57 . If you look at the norepinephrine and if that norepinephrine molecule bonds to
15:02 subtype of north american receptive, its its length to a stimulus authority protein
15:09 that will induce the production of campion, podium chinese eh and Pekka
15:16 a chinese and is responsible for phosphoric which means adding pure form molecules two
15:25 proteins. And by first for relating proteins that can regulate the opening time
15:30 the closing time of these proteins. if that same norepinephrine molecule and these
15:36 receptors, the beta receptor and alpha receptor can be co expressed in the
15:41 patch of the number and in the synods if that norepinephrine molecule binds to
15:46 to its link to inhibit there's you complex and that will actually inhibit the
15:52 of cycling campy and reduce the presence protein kind and saying this is a
15:57 pull mechanism. One of them is to produce more cycling camping. Another
16:01 is pulling the system away So they the opposing actions. Yes, but
16:06 it's not as much in regulating the crossing across plasma member and influencing the
16:12 of the member and potential but rather this activity to the secretary messenger to
16:18 secondary messenger cascades have converged on the a factor molecules cycling campaign protein final
16:25 . Now you're regulating this by two receptor subtypes that is the same
16:31 the same neurotransmitter and juxtaposition to kindness inside the South. You also have
16:39 cases and hospitalizations are responsible for defence relating or removing that peel for groups
16:45 so a lot of the intracellular secondary interactions from these Ukrainian couple of complexes
16:52 the amounts relative amounts in space and time of kindnesses and foster cases.
16:59 was for relating and hospitals is defense different proteins and molecules in the separate
17:06 . Um Yeah Northern Afrin and serotonin acetylcholine. And all of these are
17:15 immune molecules that we're discussing are very from the nino acid neurotransmitters. And
17:22 reason for it is because if you in the frontal lobe there will be
17:27 innate expressing neurons. Criminal cells exhibit lot of glutamate. There's glutamate in
17:33 spinal cord and there's there's sort of that will glutamine, glutamate and gaba
17:39 same with Gabba Gabba major inhibitory neurotransmitter the cns. You'll have south peppered
17:47 throughout the C. N. That will express gaba but that's not
17:51 case with their means nor not from example has a patch in the brain
17:59 that's called local serious. The nucleus serious. There are so much of
18:06 neurons that will synthesize and produce north and you will not find any neuron
18:13 in the cortex or in this arab or in the spinal cord. No
18:18 will be synthesizing that molly with the from local civilians will be far
18:24 quite diffuse and quite spread out throughout cortex, cerebellum and also in the
18:32 . So if you were to literally uh do a surgery or have an
18:37 , let's say a knife injury that and eliminates this portion of the brain
18:43 . Just this one small nucleus, say just gets removed by accident by
18:48 bullet, there would no be no norepinephrine in the brain. But if
18:55 bullet pierced through the frontal cortex but throughout the entire cortex it would still
19:01 glutamate and Gaba released and expressed all the CNN's the same cases with
19:09 you have raffi nuclear here in purple will supply serotonin to all of the
19:15 , sub cortex, basal ganglia then you have the raffi nuclear located
19:20 a slightly different locations and the brain will supply the spinal cord. So
19:29 look at some of the other important that you should know. This is
19:36 magna cellular basil for brain nuclei which expressing a single column. So that
19:44 that civil Colin neurons that express the that are located that only and then
19:52 will project the Seattle combing these cohen projections. So think about the
19:58 You're putting a cyclical industries inhibitor. do you think it's going to be
20:07 somebody swallows a pill in the process blood brain barrier, where do you
20:11 it's going to end up going to to one blood vessel to one part
20:15 the brain? You know? You this whole circulatory system in the
20:20 We don't have time to go over . You have this beautiful circle of
20:24 , distributes the brain that sits at base of the brain. That savior
20:31 the brain cardiovascular system. Because circle actually provides circle afloat, much like
20:37 would have a circle on the traffic with multiple exits. So one this
20:43 you can still exit and enter the about the brain still works. One
20:48 the probably most beautiful structures for Their anatomical in the brain as a
20:53 of Willis. Uh Not on the , but something for everybody to
20:58 And look into. So you have colon ergic neurons here. And so
21:04 does this where does the truck It gets into the brain gets into
21:07 blood. Given to the circle of . It goes everywhere. Vanessa's
21:16 Uh senor God. As you swallow pill, It's in your blood.
21:22 is it relevant? A single colonoscopy inevitable. It's rather than, What
21:31 you say? What we're talking about cns? Okay, swallowed up and
21:41 . Went into your blood. You calling this an inhibitor. Where is
21:47 relevant? Is it relevant to Uh huh. Is it relevant to
21:55 so famous that produced a single It is no where is it
22:06 Neuromuscular junction. We're talking about N. S. The mountains.
22:13 houses only why? Because that's where get released. It doesn't matter that
22:21 are widely distributed and get sprinkled throughout cortex. They're still within synopsis,
22:27 still gets released within seven oz. now you're a drug that answered into
22:32 blood, into the brain, goes . That concentration of the blood of
22:38 drug and the pill that gets partly destroyed, digested out before it gets
22:45 the blood? A portion of it into the brain. It now gets
22:49 through alcohol brain. There's no specific . There's no drug right now that
22:54 can take as a pill and will only to the frontal neurons versus the
23:00 all neurons. It will go everywhere it's only relevant where there's that
23:05 where do you find this little polling find it in the synopsis? If
23:10 wanted to adjust? If you wanted adjust the synthesis and you have to
23:16 about how do I make these dying synthesis? More subtle poli this should
23:24 a strategy that should be pursued. what is happening then? An alzheimer's
23:28 ? You're losing Colin ergic neurons. means that the synopsis that these projections
23:35 come from the nuclei that make a Ian including this one uh particular can
23:46 kill upon thine. Don't kill Apollo is better, as you said with
23:50 British accent trying to get it right don't feel upon times lateral golf.
23:58 take mental nuclei T A lateral So L. D. T.
24:06 . Nuclear anyways so these neurons are and that's unfortunate. Right? So
24:12 trying to introduce a strategy. So strategy then should be also how do
24:18 preserve going under time? Why are doing? Why the most vulnerable to
24:25 other pathologies that we discussed tangles Right. So all of these are
24:32 questions for you. They're not quiz real answers to them. You will
24:38 up with these answers in the next decades. But this gives you a
24:43 good understanding of signaling in the brain how these very specific molecules like dopamine
24:51 eventually take mental area and substantial Migros for dopamine expression. So if you
24:58 this area of the brain but the penetrates this nucleus and destroys the south
25:04 there would be a lack of So can you feed people a single
25:11 ? Right. Does it get into brain or does it all stay in
25:16 gut? You know? So All these things are very relevant. I
25:21 it's very relevant to just general awareness everything that's going on around us with
25:28 especially and how you use drugs and you in the future develop pharmacological different
25:35 treatments and approaches and they can harmonize the gas is not the stocks in
25:41 carbon monoxide. They function in different and the retrograde fashion. We discussed
25:46 when there is a lot of deep and either dramaturgical Gabbard pre synaptic terminals
25:52 polarization. This will induce production of cannabinoids which will travel through the plasma
26:00 not stored in the vesicles and will Lee buying two CB 1 receptors which
26:06 G protein coupled cascade will shut down channel an influx of calcium will then
26:14 the influx of calcium will then reduce vesicular release and that's why you have
26:18 polarization induced suppression of inhibition. It gabba release or deep polarization induced suppression
26:25 excitation that controls glutamate release also. in this retrograde fashion under the nominees
26:31 produced when there are heightened levels of and essentially regulate and balance the release
26:36 excited turning inhibitory neurotransmitters and you know Through CB one receptors CB one receptor
26:44 cause us the bliss the euphoria feeling runner's high feeling that comes from the
26:49 avenue is because they get produced as body is working out intensely or running
26:56 . This will be through CB one CB two receptors will discuss later and
27:01 course but right now we'll mention that mostly expressed on glial cells and especially
27:06 the micro glial cells and they are in regulation of inflammation and pro inflammatory
27:13 released by microwave. So it's CB receptors are concerned with vast neural transmission
27:19 balancing of Gaba and glutamate. CB receptors are concerned with slower processes such
27:25 the control of the inflammatory processes in brain. These are the major endocannabinoid
27:31 and two A. G. And delta nine tetrahydrocannabinol. And as I
27:37 last time Canada's plant, the marijuana , the hemp plant cannabis plant period
27:44 the civic version of Delta nine The plant itself has a scent is
27:50 delta nine THC a cent days and produces the citic version of Delta nine
27:57 which is actually non psychotropic. Now Delta nine THC is a naturally occurring
28:04 cannabinoid that has a bond at the carbon between ninth and 10th carbon.
28:10 I always like to talk about things are natural and things that are synthetic
28:15 the cannabinoids are natural from your body cannabinoids such as THC a delta nine
28:22 a Delta nine THC are natural from plan produced when you go outside to
28:29 festival. So you go to the stations or you see signs that the
28:35 shops Delta eight THC carry delta eight . Canada's plant does not produce DELTA
28:43 THC. There's no DELTA H. . H. C. A.
28:48 . So how does the FAA TC about actually gets produced from CBD.
28:54 if we take the other phyto cannabinoids is can never die. All it's
28:58 second most prevalent cannabinoids. Fighter cannabinoids cannabis plant and it's a semi synthetic
29:04 . It converts and moves that bond 9 10 to 89 carbon and makes
29:10 into delta eight THC. Which is a semi synthetic form of delta nine
29:19 . And it's unregulated. That's why see signs for sale. It's unknown
29:26 unknown. As far as we the Delta nine and CBD have therapeutic
29:30 properties. You don't know any therapeutic of delta a semi synthetic which means
29:39 Every lab may use a slightly different of conversion Delta nine into Delta
29:47 That means that during that process there be solvent are the things chemicals
29:55 it may remain in that outside and plant wouldn't produce these chemicals naturally when
30:01 presume smell to mine. And so is a cautionary note to find out
30:07 any of you in the circle. with our from the scalp and eighth
30:11 to find out what it really And it is really a semi synthetic
30:16 and it will cause half of that intoxicating effect. But I believe in
30:23 different way and then rather unpleasant way another thing to know is that synthetic
30:31 in general are a lot more dangerous they can be a lot more potent
30:37 natural mode. So synthetic cannabinoids which still be found, there's no enough
30:44 for regulators to catch them and regulate . Spice kush K to whatever Sullivan
30:50 shops. It's synthetic phenomena that gets on some plant matter. They have
30:56 affinity to the CB one receptors that times greater. So if you
31:04 let's say if you have 1000 intoxicating from alcohol or from Canada's This is
31:12 of legal states and some of your 21 or some of you have access
31:17 legal status of medicinal but now or experience where you were kind of a
31:24 altered not try to multiply 1000 times feeling it's basically can be incapacitating,
31:33 be deadly and can actually cause long consequences from single or few uses because
31:40 a synthetic molecules that cannot be processed same way about the body that have
31:45 been found in nature. They don't evolutionarily with us. But rather than
31:51 from different chemical designer molecules in the . This is a cautionary.
31:57 because in Houston there were over two people that died in Hermann Park a
32:01 years ago when somebody spread some of synthetic cannabinoids, synthetic cannabinoids, synthetic
32:09 . It's a flawed term synthetic Yes, synthetic marijuana is the same
32:14 saying synthetic sunflower plans. It does exist. Okay, so it's nobody
32:21 take and synthesize a plant and put together for molecules but you can take
32:27 molecules powders like the yellow mixed and with temperatures, put solvents and so
32:34 and gets to all sorts of different that are currently unregulated. And so
32:40 state of texas has a medical Canada's . We'll talk about it later.
32:44 of course and it's really about regulation delta nine THC. It also has
32:49 hemp program on hemp part of Canada's that don't produce large amounts of
32:55 It's regulated also for THC on the fighter cannabinoid which is CBD or
33:01 And that CBD or cannabidiol is regulated regulated by the state of texas by
33:07 individually and can be freely grown and . So, know your cannabinoids.
33:14 , you're a cannabis as this therapeutic in the signaling molecules are going to
33:22 very much looked at in the future trials for multiple different applications. Right
33:27 , the state of Texas decided that , his medicine for over 200 conditions
33:34 is not really proven. And the of California decided this medicine for any
33:42 medicinal. So we also have to developing this understanding that this is an
33:49 molecule and this unusual plant because if had anti cancer, it was patented
33:58 anti inflammatories. It was used as anti epileptic, a shot of
34:04 you know, it's not, it's . So THC has a psychotropic
34:11 But it also has these therapeutic therapeutic of distinguishing medicinal from adult use or
34:19 Canada's and what it can do. also how things get muffled because people
34:26 it for adults or recreational purposes and actually see therapeutic effects. Or they're
34:32 to use it for therapeutic purposes and don't like getting high. Okay so
34:38 all sorts of situations happening right now the world related to cannabis. This
34:44 our favorite. I mean acid neurotransmitter glue to make atomic acid, it
34:50 darker box elated by God. Which dick of oscillation is simply the process
34:54 removing the acidic cielo age group and it into Gaba. So all of
35:00 inhibitory into neurons that release gamma will in positive for God. The cycling
35:07 glutamate is not unique to glue A. So you have the same
35:10 for Jabba. Also in the sense it needs to be transported and needs
35:15 be uploaded into vesicles needs to be . The synthesis is regulated and especially
35:20 for glutamate it is very much so by pastor glial cells. So when
35:27 gets released there are three types of a tropical filmmakers actors to which glutamate
35:35 tampon and M. D. And kind Nate hamper receptor and the
35:40 and highlight their distinguished based on their because these distinct molecules called pampa and
35:46 airplane will activate or service agonists for distinct channels. Mm. Yeah let's
35:57 about glutamate channels And uh in general acid channels And there are several concepts
36:04 pharmacology kinetic selectivity and conductance. so first of all, from the
36:11 of pharmacology, we're going to talk Tampa blue channel on this pink channel
36:18 India they're both receptor channels for google the standpoint of pharmacology. They have
36:24 distinct agonists and they have their distinct agonist and India as an agonist for
36:31 . A. Gets a little bit complex with the terrorists for antagonists.
36:34 look into the following flag kinetics. do we talk about when we talk
36:40 kinetic how fast the channel opens, fast the channel closes. When we
36:45 about channel selectivity, we talked about ions crossed to the channel. When
36:50 look at the action potential dynamics, talked about voltage, gave it sodium
36:56 the channel vault, educated potassium selective . They were selected for one high
37:04 sodium, another ion potassium, both calcium channels present africa they selected for
37:12 . When you look at these channels , Ampara and an MBA. Their
37:18 for two or 3 islands. No . But now multiple ionic species,
37:27 the selectivity. When you talk about is how big is the conductors,
37:32 many ions can pass through that channel a big conductance. Because you can
37:38 again about the analogy of the water . If you have a big when
37:44 when the when the firemen come to the fire, they don't bring the
37:47 small garden hose? Bring the big . There's a lot of pressure.
37:55 how big is the hose and how of water can flow through it?
37:58 the conductance. How big is the when glutamate gets released into the glutamate
38:05 person optically emperor and NBA receptors co and expressed and glutamate will first bind
38:13 the same time to happen and the . But Emperor receptors of wrestling member
38:18 potential will open immediately. Will cause influx of sodium which will cause this
38:23 phase of excited very past synoptic potentially . And re polarization in this
38:30 P. S. P. Will because after some influx of sodium there's
38:34 to be a reflux of the casting these channels. Glutamate monster amper addressing
38:40 and potential it opens tries to de the number and then how to polarize
38:45 the numbering again. Yeah and D. A receptor channels are
38:51 First of all you can see that conduct sodium and calcium inside the cells
38:55 calcium calcium influx here is not as concerned with the polarization of the plasma
39:03 but as I noted, calcium inside south starts as a secondary messenger and
39:10 as a calcium induced calcium release So calcium is important there's influx of
39:20 but NMDA receptor doesn't open right away glutamate is released and advance the ample
39:26 receptors ample receptor opens right away and . D. A receptor does not
39:31 an NBA receptors blocked with magnesium regular concentration of extra cellular magnesium is 1.2
39:39 Ramallah and then in the A receptor a couple of binding size for that
39:44 to go inside the channel and basically it closed. So what needs to
39:51 is that this magnesium block needs to alleviated. And the way that this
39:55 is the plasma membrane from resting membrane of about negative 65 no balls has
40:01 de polarize to about minus 15 minus minus 30 million volts. And as
40:09 plasma membrane D polarizes, magnesium will NMDA receptor channel and will cause allow
40:17 an influx of sodium and calcium. an M. D. A receptor
40:22 is going to be responsible for the phase of this excited terrapass synaptic
40:28 So where does this deep polarization come ? This? Deep polarization comes from
40:33 receptors. So amber opening an influx sodium will cause the polarization which will
40:40 the alleviation of magnesium block. In M. D. A receptor it
40:44 has good um a bound to it now it will cost conduct consider an
40:48 . D. A receptor. Not an M. D.
40:52 A lot of time sample and kind to group together and they called nine
40:56 M. D. A receptor is they have these different kinetics and it's
41:01 because of them the receptors a matter tropic or something don't confuse it with
41:05 . This is notable tropical item This is an M. B.
41:08 . And M. D. A is not coupled to do bird in
41:11 I just I dunno tropic but it different kinetics and has different dynamics.
41:17 stands for appropriate tannic acid climate, an NBA receptors. There conductance is
41:22 the order of about 20 people. for China And an NBA Foster alaric
41:29 channel conductance is about 50 peter So an NBA channel in a
41:36 apple gets activated first then there's the , then you engage in MD A
41:42 then you get 2.5 times more excited be conducted Because it's 50 people.
41:49 over 20 people simmons your channel they their own antagonists or blockers sample kind
41:55 will get blocked or antagonized by molecule C N Q X. An
42:00 D. A will be blocked by PV. And sometimes it's a P
42:05 . This is roman numeral five really a Tv or a P five.
42:09 used interchangeably when glutamate is released. all that is necessary for anna tropical
42:18 a major center to open but that not all that is necessary for an
42:23 . D. A. I am tropical with a major septic field.
42:28 an interesting thing that it plays a first of all inside the synapse you
42:33 some licensing, we learned about licenses inhibitory neurotransmitter and the spinal cord licensing
42:40 also a co factor for an D. A receptor. That means
42:43 the certain amount. Well I see to be present and the synapses in
42:49 for this glutamate to effectively mind I walk into fit into key chain effectively
42:55 the NMDA receptor. Uh huh. other thing is it's a coincidence detector
43:03 is an NBA receptacle coincident defector? it needs pre synaptic glutamate. So
43:09 detects pre synaptic activity and it needs synaptic deep polarization so it detects passing
43:17 pre synaptic we made it binds the but it won't function until it senses
43:24 synoptic deep polarization. Uh huh. it's a coincidence detector in a way
43:30 linking the activity the priest an african activity and it is a very important
43:37 in many different forms of plasticity which the cellular mechanisms for learning and
43:45 Once an M. D. A is open it will allow for influx
43:48 sodium and calcium and influx of There's a couple of binding sites from
43:54 there's a binding site for a sink well. And a common street drug
44:00 or Angel dust also has a binding to an NBA receptor and pharmaceutical pharmacological
44:08 also have binding sites in NBA So then the receptor is a huge
44:14 for different things mostly for therapeutical applications obviously for and illicit street drugs as
44:23 . PCP binding to an M. . A receptor can cause hallucinations and
44:28 and state of acute schizophrenia which can into chronic schizophrenia that that is evident
44:37 quite a lot of the illicit drug reported from this drug. So it's
44:43 potent one time the fact that it's powerful on that door may mess up
44:49 door for a long time. So you don't use the right key you
44:55 you sometimes forced the key in and try to kind of push your way
44:59 and then the lock is broken. it doesn't block anymore, stays half
45:05 or stays closed all the time and have to slam it every time to
45:09 up. And now you have to the door and do some magic
45:12 Turn it three times to wait for click and remedial. That's just an
45:17 . But that's the reality again, that these powerful synthetic molecules they bind
45:24 these receptors bind to these doors and they get unbound even the effect can
45:31 long lasting. This is the metal intimate receptors that are linked through june
45:37 couple of cascades and we'll look at in the second. You guys remember
45:42 it to this technique called a voltage technique and the voltage clamp technique was
45:47 in order for us to isolate the and to measure russell potential for individual
45:54 and we use voltage clamp and Hoskin hostile use voltage plant in order to
45:59 that inward sodium Karen outward potassium They showed the reversal potentials for these
46:06 . They use specific blockers to block the inward are the outward fern.
46:11 so this is a voltage clamp experiment an M. D. A receptor
46:16 the left. You have normal physiological In which you have 1.2 million moller
46:24 outside of the next solution. And you apply glutamate and you record from
46:30 NMDA receptors and this is an MDA current but minus 60. These downward
46:38 should be opening of an M. . A receptor and as you can
46:41 there's no activity here the moment 60 compared to here there's a lot of
46:48 here at -60. This is a condition -30. You can see some
46:56 the activity here And at zero you nothing. So you're recording through an
47:05 . D. A receptor. And in this course we learned the nearest
47:10 . The first equation was equilibrium potential for individual ions. My Mercedes for
47:18 positive 55 for sodium positive, 125 for calcium. This is the reversal
47:27 for NMDA receptor with zero and an . D. A receptor is
47:35 To three aisles One potassium -80 sodium 55 calcium 125 for yourself. So
47:48 reversal potential in these receptor channel somewhat a reflection of relative concentrations and flexes
47:56 ions through these specific channels. Okay it cannot just be calculated. It
48:04 to be measured. Once it's measured it can be applied and calculated in
48:10 reverse manner. Once you d polarize south to positive 30 positive 60.
48:15 does not really happen physiologically. But can see that these channels are very
48:20 d. Polarized potentials in voltage And then you repeat the same experiment
48:25 you remove magnesium from extra cellular That means there's no magnesium and an
48:30 . D. A receptor in the of looting made at minus 60 mil
48:35 . It's opening and it's opening a and it's staying open a lot.
48:41 you remove magnesium you have massive deep . Is that massive activation of NMDA
48:48 ? zero. Magnesium is also a for hyper excitability, seizures and
48:55 Because if you remove magnesium now and M. D. A receptor gets
49:00 with all of the glutamate being D. Polarizes lots of conductance causes
49:06 activity causes synchrony. And so it's important that an M. B.
49:11 . And magnesium levels and NBA Magnesium levels are being shot them extra
49:17 solution all of the time. So where acetylcholine receptor reverses. Zero.
49:27 vault. What about and play potential junction? Zero normal. What about
49:39 receptor? Zero normals. What about PSP zero normals. So that's zero
49:49 is important. And it's uh when said it's arbitrary to the outside the
49:55 value. It's interesting how some of major components of the system would fall
50:01 that zero value that we chose Another . Remember I. Ve plots ivy
50:12 are I stands for current and the for voltage. So if you have
50:18 current here in this direction it's inward and the positive fecal sample values represent
50:25 currents. Now we're going to use crime and I'm gonna measure the
50:32 V. Curves for the empire which the early component E. S.
50:38 . And for an M. A. Receptor channel which is the
50:41 component of the PSP. So in experiment now we're going to use all
50:46 these brains and all of the techniques you learned in the last couple of
50:52 voltage clamp. It allows you to for potential. So it allows you
50:56 look at different currents, allows you use pharmacology to belong different kinds of
51:01 potential. Good with that. This blip here is is stimulating releasing
51:07 Not just stimulus is you're releasing glutamate there's little blip here and then you're
51:12 for synaptic response and fasten optical. see this inward current coming in and
51:20 you say, okay I know what gonna do is I'm gonna measure this
51:24 component. The non an M. . A component which is ample Kinney
51:29 and I'm gonna measure it only about milliseconds following the stimulation. So just
51:36 milliseconds following the stimulus. I'm gonna this dashed line here and I'm going
51:41 take a measurement but this early So at every voltage minus 80 minus
51:48 20 0 plus 20 plus for I'm going to have a measurement after
51:54 of this current. Just like you earlier when we looked at that reversals
52:00 sodium are in the action potential. these triangles either closed or filled or
52:10 Is the measurement for the early component says that the -100. There was
52:15 lot of this early -40. It to zero. It reversed. There's
52:22 current zero million. Also the early . Just approving that ample which is
52:27 early component reverses its zero more And then it continued a millimeter like
52:34 . So now you have not only but now you have a deep plot
52:38 is the linear plot for the early which is ampara receptor component in that
52:48 experiment. I'm also gonna say I'm interested in measuring the length opponent.
52:54 I want to have an ivy plot the late component. Leave component as
53:00 NBA. This after channel as I to you and I'm going to take
53:03 second dash line measurement maybe about 20 following the stimulus. Yeah. And
53:13 at -80 of -100 At -80. is my closed closed circle here.
53:22 not seeing much current. The current close to zero at -60. I
53:27 seeing some current of -40. Is more current was a little bit more
53:32 than it reverses it zero and then closed circle here is an India conductance
53:39 the positive all the potential. Okay now I know that my leave component
53:47 NBA component has a non linear I've and it actually prefers to conduct in
53:55 outward fashion. So if I were bring the potential to zero and then
54:00 areas after would be conducting much stronger the outward fashion Then it would be
54:05 -52. The inward fashion. These all important components when you're modeling the
54:11 when you're modeling conductance is when you're to understand and mathematically recreate these conducting
54:18 models which is very important from both and theoretical perspective and now you realize
54:27 okay so what I'm measuring here is late component that this blew this whole
54:33 area under this blue curve essentially is late component is the component that comes
54:39 an M. D. A And now I'm really smart too because
54:46 know how to use voltage clown, know how to produce ivy plots So
54:52 can model and talk to friends in math department but I also am really
54:59 because I can use nerve pharmacology and I applied glutamate and stimulated and measure
55:07 lead component. I'm now going to to my friends and the pharmacology department
55:12 borrow a little bit of aptv and this a PV. And essentially when
55:18 apply a PV this whole blue component going to disappear and going to get
55:25 and if you repeat the measurement of late component in the presence of a
55:31 which is an NMDA receptor blocker. can again measure the early component and
55:37 or filled in open triangles. It matter. Doesn't affect early component at
55:43 because this block is specific to nmB specific to the late component of the
55:50 . But when you apply it you these open circles on the lead component
55:55 this is the curve For the block NBA receptive delayed component which was essentially
56:01 to zero line mm biology. Nothing is zero. It doesn't stay at
56:06 for long. Always fluctuates. So a little bit of remaining current here
56:12 small but it's very close to zero and that tells you that this is
56:17 P. D. Is a specific . It to the late component is
56:21 specific block. It and N. . A component and it does not
56:26 the early component and two component but will block this nonlinear played an
56:31 A component of the PSP. Great an exam questions from this but but
56:42 think that if you understood the voltage you understood the ivies in the
56:47 This is all coming together nicely for . Yeah Glutamate gated channels calcium intelligently
56:57 several locations so we talked about Still Colin we're talking about Gleiberman.
57:06 gonna talk about Gabba today. So have a few more slides to go
57:11 . And if you look at the receptors which are ruminate receptors. But
57:16 mentioned in the previous slide as I that all in NBA receptors impermeable with
57:20 calcium but only certain Emperor receptor supermodel the council. All permissible to sodium
57:26 potassium but only certain Emperor receptor supermodel the council. And now if you
57:31 we studied the trans membrane segments and voltage gated sodium channels as one as
57:36 as three or four. So now looking at this glutamate receptor channel which
57:42 a number of subunits. Um has trans membrane M. One M two
57:46 three and four does remembering segments. is a very large sequence of amino
57:54 sequence and long sequence three dimensional. ordinary Centenary structures, false sheets.
58:04 how important is one amino acid in sequence. It can be very important
58:12 the sequence of Emperor receptor has a . In it which stands for glutamate
58:17 an additive uh emperor receptor. It allow for calcium conductance. So if
58:23 apply glutamate can you measure uh sodium ? Who detect sodium conductance? Yeah
58:32 is an emperor sector. So you sodium conductance and you're also detecting a
58:38 calcium conductance here. But if you in that very long I mean as
58:45 chain and substitute or removed. And substituted with arginine. Are you
58:53 now apply glutamate and you'll still see currents but there will no longer be
59:00 calcium flux is through that channel. how important are these sequences going back
59:10 roderick Mackinnon studies Identifying sequences that gate and closing of the channel. Now
59:18 talking about one it's not closing and of the channel, but one amino
59:24 decides whether this channel will allow for or not. Remember calcium is not
59:28 much about changing number of potential as as changing the intracellular processes inside the
59:36 that's really potent. Again we go to that same lock and key
59:42 you messed up one tiny piece of lock and that's it. The door
59:47 no longer open or it doesn't open . Montecatini is a development. And
59:57 enough when we talk about the developing CMS synopsis, they only contain an
60:02 . D. A receptor is they have amperage separates. Glutamate gets released
60:07 the synopsis and the synopsis are referred in called a silent synopsis. Why
60:13 they silent because you need a lot deep polarization in order to open those
60:20 M. D. A receptor And there's glutamate that is being
60:24 There's no ample receptors to cause the deep polarization. And so the synopsis
60:28 silent and those synapses during early development be woken up a very large deep
60:35 stimuli. External stimuli internal chemical stimuli not just by minute, minute
60:42 And excited terry synopsis. Um And . D. A receptor has sub
60:50 . And uh and R. two R. to be at the sub
60:55 . And remember that these proteins are up of multiple different subunits groups.
61:06 and these multiple different sub units shift their composition So there could be two
61:14 to beta and gamma. And then are the predominant receptors of day one
61:22 birth and the date 21 Post They rearrange they rearrange the subunits so
61:29 ratio on our 28 and are to changes cellular location and activity dependent Obviously
61:37 NBA receptors a coincidence detector. It's activity, detective activity increased on that
61:42 can cost an active activity. There changes in the expression and AMP on
61:48 M. D. A. Receptor ample receptors And the receptors can also
61:54 located extra synaptic allowed outside the synaptic . I'm for receptor in particular is
62:00 fast and it can travel through this mosaic membrane into the synopsis. Can
62:05 imported in the way into the synopsis it can travel micro meters in milliseconds
62:15 travels very fast. So when you about cellular protein channels that are insertions
62:21 inside it's one way to enhance that . Remember it's all do that glia
62:26 control the amount of modem empathy is for neurons. Mhm. And now
62:32 plus synaptic neuron is like I want be active. I want to be
62:35 . I'm not getting enough blood to that that that pre synaptic neuron is
62:41 me down. Mhm. But I my own powers fasten attic neuron.
62:47 own power is I'm gonna import more receptors into the synapse more than the
62:56 . Why? Because just a little and made now is still going to
62:59 significant for me. So these are pre synaptic fasten optic strategies. An
63:05 on an NBA can both move through numbering. They don't need to be
63:09 inserted from the cell into the An ample moves fast and an
63:16 D. A receptor is tied to different forms of plasticity. We talked
63:21 on in this course that you can certain synopsis or potentially ate them.
63:26 become stronger potential hated that potentially asian be long term and sustained and you
63:33 also depress, weaken synapses or eliminate altogether. The ones that are not
63:39 . So you have this depression also be long lasting. We also talked
63:45 spike timing dependent plasticity which is the between the pre synaptic activity and parson
63:52 response and M. D. A . Pre synaptic activity And the textbooks
63:58 responses placed very perfectly at the intersection what some of the necessary mechanisms for
64:05 south to have these forms of Whether the short term long term forms
64:10 plasticity that's why it's activity dependent Its activity dependent learning if you start
64:16 wall you don't learn much, there's much activity on an empty wife wall
64:23 activity dependent processes activity dependent learning linking synaptic vipassana, linking pre synaptic signaling
64:32 chemicals blew them A plus and that motivate response, spike timing dependent plasticity
64:40 an MBA is very very important for forms of this plasticity. And you
64:44 see in the review articles if you scientific literature and the few articles you
64:50 see even separate sections for an D. A. Dependent and
64:55 D. A. Receptor an D. A. Dependent plasticity plasticity
65:00 models and rules for the south's that based on an NBA areas after.
65:06 . By the way, I don't time maybe today but maybe sometime in
65:12 future I'd like to remind you that you walk onto uhh libraries using your
65:18 and that idea and password, you access so much cool literature, original
65:24 , review articles, books, some old you can borrow things that
65:31 doesn't have through what is called inter loan. So you find something you
65:37 know it's not at us and says you can actually access it because you
65:41 a choice will have an agreement with medical center library with other libraries that
65:46 larger national libraries and you can get really cool article. But let's say
65:52 want to Look at 1920s article you probably get it uh in pdf in
65:59 two days or so by this If it's not available to you immediately
66:05 uh look up pop mod and started up through some of the articles.
66:11 started talking about this because a lot times students are scared of reading the
66:18 and when you download a special an is your undergraduate student you are very
66:24 maybe. Uh and that is something just comes with time and territory like
66:32 everything you have to learn, you how you first pick up an app
66:35 for parking and you're confused and where the zone number that I enter?
66:39 it's just going to work. Am going to get a ticket? You
66:42 as a reminder gonna go through and on the fifth time your parking,
66:45 know the zone is there, you're away all cool. You know,
66:50 coming through you know it's easier. the same way the scientific literature,
66:55 police authority pickles and if it's intimidating a couple of things, read the
67:02 . And a lot of the modern will have a graphic graphical abstract which
67:09 in a very quick way, should able to convey information mouse molecule X
67:16 this cell. Did this. This really what you're going to read
67:21 So if you can understand the abstract you can understand the graphical abstract do
67:27 first. And if you're ever entering a new area, a new protein
67:35 molecule model disease always go to review first because review articles will broadly explain
67:42 you what is this? What is X. It will broadly explain to
67:49 . Then go to original scientific literature say you're hunting for the new molecule
67:53 something but it's very complex and so get scared and you're like, I'm
67:59 gonna do this. All right you at the last minute and then you
68:02 remember something 15 minutes, answer the or answer questions and you're gone.
68:08 understand the graphical concept the abstract. next thing you do is you go
68:13 figures. Read the material and look the figures and that's when you go
68:20 to methods. A lot of students the abstract and a lot of journal
68:24 will have abstracting and methods. You reading methods C N. Q X
68:29 P. D. Magnesium zero. like what in the world? But
68:34 read the thing is we wanted to in an epilepsy model, this is
68:38 figure. And then what is the tomorrow you go back and say okay
68:42 zero magnesium and that opens an NBA . Now you understand the methods behind
68:48 the last word of advice if you to read the literature will be is
68:54 discussion section allows for scientists to predict to fantasize to excuse themselves by saying
69:03 is not perfect work by no So please don't hold me fully for
69:10 . There's going to be better students my lab will be even better
69:15 Okay, predict because we saw this we partly prove the hypothesis. We
69:22 the answer to the next secret The number's gone behind the next corner
69:29 fantasize If I had $1 million dollars a billion dollars. Mhm. And
69:38 I say sky is the limit, is no longer the limit right
69:43 Three dudes been there already. What they for? More than three And
69:49 too. There's a mosque Branson of . Who's going to get me 1st
70:01 now you know the Sky's going around to live in two. So this
70:05 with the discussion section. If you're for new trends, I have an
70:11 from somebody telling you like what are new trends And Alzheimer's disease discussion
70:16 Review articles a lot of times at end. Well, where are we
70:19 with this kind of? What's the of this therapy electromagnetic simulation. What's
70:24 future of this? And you're oh the future? What's interesting for
70:28 , you know? So anyways let's on this path. Oh my
70:33 I'm running out of time trying to to the medical tropic signaling. But
70:39 the google make receptor binds to the tropic receptive will activate this cascade here
70:45 P. I. P. It will split this P.
70:47 P. Two molecule one that will membrane bound Dia sollecito de Gea.
70:53 one. But we'll go into cytoplasm hospital triphosphate I. P.
70:57 I'd be three will bind to the . P. Three receptor calcium channels
71:02 is located in smooth and the plasma and cause further release of calcium.
71:07 you have the calcium induced calcium release for cellular early And this dag will
71:13 with protein kinase C. And calcium interact and rev up and start activating
71:19 kindnesses. Calcium module, independent And in all of these cascades medical
71:25 cascades will be regulating the amounts of kindnesses post thoroughly and foster tasers to
71:32 correlate the challenge. Gaba particular gobble channel. Yeah. To a channel
71:38 iron. A tropic Gaba receptor When gabble binds to Gaba receptor,
71:44 happens when it binds to the Gaba receptor? Gabble binding will cause influx
71:51 chloride and you will have hyper Gabby is a medical tropic G protein
71:59 receptors. So typically they have seven member in sub units and activation of
72:05 receptor by goblin can cost two things open potassium channel and cause influx of
72:12 more hyper polarization or this is prison or Priest pasin article and Prison
72:19 It can block calcium channels so it regulate neurotransmitter release. Hang with me
72:26 a second. Let's first look at very popular channel. A lot of
72:33 bond to that channel if you want increase inhibition in the brain If there's
72:38 much excitation you know the child is and running around give them drugs given
72:46 put him down arbitrary, it's it's active. Too busy. A PhD
72:51 . Let's do it. We'll get at school to give a DVD medications
72:56 some counties. So what is Gaba inhibition? Okay so the brain activity
73:05 inhibited benzodiazepines. Benzos will buy into . There's a very classic anti epileptic
73:12 seizure medications. There's no anti epileptic . This is anticonvulsant drugs.
73:18 it's a seizure and anticonvulsant medication and stop seizures by increasing inhibition. Barbiturates
73:25 put you down uh sedatives, they through the Gabba reception there steroids also
73:34 and control of information Also I think Gaba a receptor that's an all martini
73:42 hour, One or two causes So usually a person is quiet three
73:48 4 dancing on the table. Too inhibition. We have desensitization and you
73:56 disinhibition of inhibition. So all of are targeting Gaba a receptor and chloride
74:05 . Yeah baby receptors linked to g complex. And if you look at
74:11 Gabba and Gabba be signaling. This some of the work that I did
74:16 I was a crazy graduate student we the cells and you can see the
74:21 . P. S be excited for response here immediately. The C.
74:25 . S. P. Gets checked Gaba a mediated I PSP. The
74:29 conductance is and with some delay because the activation of jeopardy in couple of
74:34 stop turn and subsequently opening of the channel. You see further hyper polarization
74:40 was the gavel. B. What happens if you block Yabba
74:46 With the curriculum is a specific antagonist blocker for gobble A. Instead of
74:51 small response in Guam followed by Now you get this massive massive response
74:59 depressurization. So you can see how excited to inhibit their synapses and activation
75:05 excited to intercept is followed by an within the same networks. Really check
75:10 control the amount of deep polarization and polarization of these sounds. And finally
75:17 I was going to go over this which places it all together for you
75:23 I don't think I'm going to talk you anymore today and I'm going to
75:28 it for the next lecture. But you want to review it yourself before
75:34 this is really cool diagram that puts lot of things in the perspective Gaba
75:39 inhibitory synapse. Blue dramaturgy excited tourists how the Gabba functions in the
75:46 how Gabba spillover can affect excited their . So when we come back on
75:52 we'll review this, we'll have two slides on the synaptic transmission and we
75:58 move into the cNS brain parts and and functions of the cNS. So
76:06 out for registration for your quiz this . And if there's any issues or
76:12 , please email me or dress it class on thursday. Thank you.
5999:59
-
+