| 00:03 | today we are on Wednesday october This is lecture 13 of neuroscience. |
|
| 00:09 | we're actually going to finish talking about transmission. So this is going to |
|
| 00:14 | neuro transmission for for part of this before we go into the C. |
|
| 00:20 | . S. Parts and functions. we will wrap up review some of |
|
| 00:26 | information we study the last two wrap it up with some of the |
|
| 00:31 | information and putting it all together in pretty complex diagram at the end to |
|
| 00:38 | the complexity part of this complexity and neural transmission in the C. |
|
| 00:43 | S. And then on monday you your quiz. So that quiz should |
|
| 00:48 | showing up. If not now. said it should be already showing up |
|
| 00:52 | the end of the day on It's gonna be 10 minutes long and |
|
| 00:57 | going to contain nine questions. So can prepare yourselves for the quiz and |
|
| 01:05 | quiz will contain information only on neural . So whatever we covered today on |
|
| 01:11 | parts of the C. N. and development of the C. |
|
| 01:14 | S. That's not going to be the quiz. So the quiz will |
|
| 01:19 | neural transmission 123 and four which is . Okay, when I spoke about |
|
| 01:26 | supporting lecture materials and I spoke about caging of neurotransmitters. This technique, |
|
| 01:32 | refer to the fact that there is article that you can look up but |
|
| 01:36 | never showed you that article. So just showing you that this article is |
|
| 01:40 | . I just want you to be that this is a technique on occasion |
|
| 01:45 | the neurotransmitters that spatially very precise and can be very fast and you can |
|
| 01:54 | neurotransmitters in four dimensions which gives you lot more advantage compared to this. |
|
| 02:02 | classical what you would say, dialysis electrode dialysis electrode application of certain solutions |
|
| 02:09 | neurotransmitters. So if you're interested you review it but the principle is that |
|
| 02:14 | can activate very precisely multiple synopsis almost the same time in different locations in |
|
| 02:22 | network that you're studying. Uh Now lot of our lectures focused on two |
|
| 02:31 | . We're focused on the amino acid transmission glutamate and Gaba because we're talking |
|
| 02:38 | E. P. S. S. And we're talking about I |
|
| 02:40 | PS. And we'll continue talking about today. We also focused quite a |
|
| 02:45 | on the means and we understood that means are special acetylcholine serotonin system which |
|
| 02:52 | tryptophan, five Htp hydroxy tryptophan and H. Trip trip to mean. |
|
| 02:59 | also the cata columbine system which has uh l dopa dopamine norepinephrine and epinephrine |
|
| 03:08 | you're not responsible for knowing the enzymes convert them except for everything that you |
|
| 03:15 | learned about the civil code. And you have to know the chat will |
|
| 03:19 | the civil code will break it You should know these are the major |
|
| 03:28 | . You should also know that in brain acetylcholine functions through two types of |
|
| 03:33 | in the cns sarinic uh You should also understand that they may be opposing |
|
| 03:42 | causing opposing activity. Nicotine receptor can de polarizing to the south to |
|
| 03:48 | And masculinity receptor will open a potassium through the djia protein complex. And |
|
| 03:54 | receptor is really inhibitory by physically it inhibit hyper polarized neurons. Uh The |
|
| 04:04 | I mean serotonin system and cata cola they all function through g protein coupled |
|
| 04:11 | systems. And so we will review of this and we already talked about |
|
| 04:16 | last lecture uh we said that when have ion a tropic nicotine, acetylcholine |
|
| 04:23 | muscular tonic which is medical tropic, can have opposing actions to each other |
|
| 04:28 | the same molecule. And then we at the example of norepinephrine and in |
|
| 04:33 | case it's ju protein couple signaling. how can one molecule have different |
|
| 04:38 | And we looked at the stimulatory beta receptor for norepinephrine and alpha to adjourn |
|
| 04:46 | reception. We said that beta is the system and alpha two is pulling |
|
| 04:51 | system away from producing a certain secondary which is protein kinase, a cyclic |
|
| 04:57 | and protein. We also mentioned that inter cellular signaling molecules like kindnesses will |
|
| 05:05 | for a late channels will force for late other molecules and other proteins. |
|
| 05:11 | prospectuses will defrost for a late or will remove the P. 04 |
|
| 05:16 | And so there's certain regulation of these and phosphate Asus that are important for |
|
| 05:23 | signaling downstream. When you activate these tropic signaling cascades. So you will |
|
| 05:29 | responsible for the entire pathway here, alkaline. And also the fact that |
|
| 05:34 | discussed that Colin ergic neurons are very and our new neural degenerating early during |
|
| 05:41 | alzheimer's process and alzheimer's medications will target citadel colonist. Aries. These are |
|
| 05:49 | agonist, national natural agonist acetylcholine and you have exogenous agonists and exogenous antagonists |
|
| 05:58 | nicotine IQ. And most sarinic Muscarello receptor controls the opening of potassium |
|
| 06:05 | because there are no intermediaries here between receptor g protein complex, there's no |
|
| 06:11 | enzyme involved. This is referred to the shortcut pathway. So you can |
|
| 06:17 | impact the nearby potassium channel and opening the potassium channel by mascara nick. |
|
| 06:23 | receptor Joubert in complex will cause hyper of the cells we reviewed. Cata |
|
| 06:33 | means and you should know that these are responsible for distinct functions but they |
|
| 06:41 | have overlapping functions. So we talked serotonin is responsible for mood but so |
|
| 06:45 | cata cola means in some parts but different types of mood. Now cata |
|
| 06:50 | means like dopamine are responsible for movement . So when you think about norepinephrine |
|
| 06:57 | , it's like an adrenaline of your which tunes your brain into the immediate |
|
| 07:02 | . The fight flight response. we talked about how you can um |
|
| 07:09 | the bio availability of these molecules by the enzymes that degrade them in the |
|
| 07:15 | coding system. acetylcholine histories by blocking transporters that transport these molecules back to |
|
| 07:22 | vesicles into the pre synaptic terminals that reloaded into the vesicles and essentially pharmacologically |
|
| 07:29 | entire pre synaptic post synaptic the degradation receptor binding sensitivity and all of |
|
| 07:37 | different aspects when designing different pharmacological Serotonin, the precursor, stripped a |
|
| 07:44 | . So when you have a lot turkey, turkey contains tryptophan and |
|
| 07:49 | It makes you very happy and sleepy because you're typically with friends or family |
|
| 07:54 | you're full and you know, something is happening that's relaxing. There's no |
|
| 08:00 | or tests that So um and serotonin of serotonin regulation is important for mood |
|
| 08:07 | mental disorders. So, PROzac, is antidepressant medication and others with target |
|
| 08:12 | re uptake of serotonin again, prolonging by availability which is kind of a |
|
| 08:17 | theme here. We want to prolong availability of some of the molecules mono |
|
| 08:22 | oxide. Asus are also going to cata cola means also going to process |
|
| 08:27 | of these amine molecules. We're talking serotonin and so mono amine oxidase inhibitors |
|
| 08:35 | is another way that you can target blocking the oxidase. That degrades category |
|
| 08:42 | uh and serotonin uh will prolong the of that molecule. This is the |
|
| 08:50 | pull pathway. So beta Uh is the other side. This is Alpha |
|
| 08:56 | data. A dramatic receptor is linked Gs stimulant 30 G protein complex that |
|
| 09:03 | induce the production of cyclic NPM protein say. And alpha two is linked |
|
| 09:09 | G I inhibitor G protein complex which inhibit the further production of cyclic |
|
| 09:15 | And the way pull the system away producing more of these secondary messenger |
|
| 09:22 | Remember that when we discussed the immune , we said that they're unique because |
|
| 09:28 | have the nuclei and these nuclei selma's neurons that synthesize and can synthesize these |
|
| 09:35 | . And then these molecules get distributed the external projections that are somewhat spatially |
|
| 09:42 | specific and very broadly innovating or sub cortical and spinal cord areas. |
|
| 09:49 | so if you were to literally take what was cerulean, this nucleus here |
|
| 09:53 | would not be any more norepinephrine that brain makes. But if you were |
|
| 09:58 | take out that the whole cerebellum or of the whole hemisphere, you would |
|
| 10:03 | have the other hemisphere making amino acid like glutamate gaba and all of the |
|
| 10:10 | that are expressed very widely throughout the system. And for the civil code |
|
| 10:15 | production we have this basal forebrain magnus nucleus in green and this particular |
|
| 10:22 | lateral dorsal segmental nuclei in the brain that are responsible for all of the |
|
| 10:28 | code, in that we have in cns and the cannabinoids again are |
|
| 10:33 | There's no storage in vesicles they're a bit soluble a function in retrograde |
|
| 10:38 | That means that they get released post aly rather than prison optically it will |
|
| 10:44 | . We travel to the pre synaptic will bind to the pre synaptic receptors |
|
| 10:50 | of cannabinoids to CB one cannabinoid one active as the G protein and |
|
| 10:57 | which inhibits and blocks voltage gated calcium , thereby this retrograde synthesis release and |
|
| 11:07 | of neural transmission for both. With and gaba balancing the release of glutamate |
|
| 11:13 | gaba when there are heightened increases in glutamate, ergic signaling or gaba ergic |
|
| 11:20 | . These endocannabinoid anandamide to abdominal These are endogenous molecules and then we |
|
| 11:27 | a lot of phyto cannabinoids. Phyto come from cannabis plants. Fido is |
|
| 11:33 | derived to DELTA nine THC is a cannabinoid because it can be found in |
|
| 11:40 | plant. It is not to be with synthetic cannabinoids which can be synthesized |
|
| 11:46 | in the lab or taking some of other natural phyto cannabinoid molecules precursors and |
|
| 11:53 | them into some synthetic aspect or variation that particular molecule. So DELTA eight |
|
| 12:02 | which you may see if you pull next to smoke shops and stuff is |
|
| 12:06 | synthetic molecule that's made from another cannabinoid CBD or cannabidiol. We'll talk about |
|
| 12:13 | further uh later. And of course remember that the gasses will behave in |
|
| 12:19 | similar fashion. No, the secular lipid soluble and will have retrograde respective |
|
| 12:27 | from nitrous oxide. For example, sign optically. Okay, CB one |
|
| 12:33 | are expressed on almost all of the . Ubiquitously. It's one of the |
|
| 12:39 | actually the most abundant G protein coupled CB one receptor CB two receptors you |
|
| 12:45 | learn or expressed more on glial cells are involved in other processes in the |
|
| 12:51 | . CB one is really what you're here is regulating and controlling the amount |
|
| 12:56 | exciting neural transmission is not alone. are other systems neurotransmitters such as a |
|
| 13:03 | which we already mentioned which does a type of pre synaptic release but it's |
|
| 13:10 | a denizen is controlling the excited to in a pre synaptic release. So |
|
| 13:15 | system is really interesting because it's retrograde it's balancing both the excitation and |
|
| 13:21 | Yes, you can see it as negative feedback loop. Yeah. The |
|
| 13:30 | heat there is prison optically, the in the cannabinoids get express. Plus |
|
| 13:35 | ap tickling and the CB one acts an air conditioner by shutting down the |
|
| 13:40 | influx and vesicles release. Yeah, uh amino acids. We looked into |
|
| 13:49 | acids again. Gaba is synthesized from . So all of the cells that |
|
| 13:54 | gaba, all of the inhibitory cells they have inhibitory neurotransmitter gaba, they |
|
| 14:01 | express the atomic acid decoder box Alice God. And glutamate will have its |
|
| 14:06 | loading properties. Transporters into the cells transporters into the vesicles gaba will have |
|
| 14:13 | own transporters into the pre synaptic neurons into the vesicles and also the other |
|
| 14:20 | that we talked about that glia controls amount of glutamate that is available to |
|
| 14:26 | . So we discussed this tripartite synapse we said that glia is capable of |
|
| 14:33 | glutamate during the dramaturgical signaling if you remember, it's in uh the previous |
|
| 14:41 | lecture. Let me find it. so this is the tripartite synapse. |
|
| 14:48 | has three parts the pre synaptic neuron one post synaptic neuron part to |
|
| 14:54 | the third part. And when glutamate released, glutamate will bind to |
|
| 14:58 | a tropic and medical tropic receptors and started learning a little bit about the |
|
| 15:02 | tropic receptors and receptors. And we'll that today again glutamate gets released and |
|
| 15:08 | has a glutamate transporter that's neuronal that transport it back into the south, |
|
| 15:14 | the upload of it into the vesicles subsequent release. But glee ourselves have |
|
| 15:20 | own glutamate transporters and they will suck glutamate and with will turn it into |
|
| 15:26 | and then we'll control how much of gets passed back onto neurons And the |
|
| 15:30 | of glutamine will with glue taman eyes and some energy will convert it into |
|
| 15:37 | and upload it into the vesicles. here it's very evident that glia will |
|
| 15:42 | control of that availability of glutamate. amount of glutamate and glial processes such |
|
| 15:49 | transport or some dysfunctions. Real glutamate can have a significant effect on the |
|
| 15:57 | on the of the brain tissue and communication between neurons. Okay, so |
|
| 16:08 | that slide was a little bit Now when we talked about glutamate we |
|
| 16:12 | that glutamate combined to AMP A. M. D. A. And |
|
| 16:16 | eight receptors. They all have their agonists and they have their own respective |
|
| 16:22 | antagonists. We started talking about P. S. D. And |
|
| 16:29 | talked about E. P. P. Initial phase of E. |
|
| 16:32 | . S. P. This deep comes from amper receptors and the slave |
|
| 16:40 | of E P. S. Comes from N. M. |
|
| 16:44 | A receptors. So this entire thing . P. S. P. |
|
| 16:53 | . Are anywhere between let's say 10 10 to 20 milliseconds in duration. |
|
| 17:05 | this is the excitatory post synaptic So when glutamate is released from the |
|
| 17:11 | terminals it will bind to amparA and NBA receptors. And first ample receptors |
|
| 17:18 | going to open because ample receptors only the binding of glutamate and India receptors |
|
| 17:24 | going to open only after ample receptors been activated because NMDA receptors have a |
|
| 17:31 | block here and and NBA suffers need have this change in membrane potential to |
|
| 17:39 | place from resting membrane potential into more polarized levels in order to alleviate the |
|
| 17:45 | block. So with deep polarization magnesium get kicked out of this channel. |
|
| 17:51 | now an NBA channels will conduct significant of sodium and calcium inside the south |
|
| 17:57 | also allow for the potassium influx. the initial deep polarization and sodium and |
|
| 18:05 | and calcium is the deep polarization part subsequently the fluxus the potassium leaving the |
|
| 18:13 | are responsible for the re polarization part this E. P. S. |
|
| 18:19 | . And it has as I said components. So when ample receptors are |
|
| 18:23 | they'll conduct 20 pick A seaman's and . D. A receptor is much |
|
| 18:27 | conductance of ions. They have their respective antagonists or blockers, ample |
|
| 18:33 | It is blocked by C. Q. X. And M. |
|
| 18:36 | . A. Is blocked by a . B. And M. |
|
| 18:39 | A receptor is a coincidence detector because needs to coincidentally detect pre synaptic glutamate |
|
| 18:47 | and post synaptic polarization. So it's . Dentally if you have glutamate, |
|
| 18:53 | have glutamate, do I have deep ? There's no deep polarization. I'm |
|
| 18:58 | coincidentally detected synaptic personality activity and then receptors do not engage. So you |
|
| 19:04 | to have the personality deep polarization for M. D. A receptor still |
|
| 19:08 | you also need to have licensing as co factor that can bind to the |
|
| 19:15 | receptors to make the glutamate binding and of the channel fully effective. So |
|
| 19:21 | in the cns lie scene is the factor for an M. B. |
|
| 19:26 | receptor and then the spinal cord let's molecule is a major inhibitor neurotransmitter. |
|
| 19:32 | here it's a co factor for excitatory for synaptic signaling. So and then |
|
| 19:39 | receptors are ion a tropic receptor channels they have slower kinetics they're blocked with |
|
| 19:47 | and they're not to be confused with but tropic uh glutamate receptor g protein |
|
| 19:56 | and uh also to note that in of the cases and NBA receptors a |
|
| 20:04 | to calcium and only in some cases can cross through the opera receptions. |
|
| 20:11 | there are certain I discussed mentioned MK 21 is an antagonist for an |
|
| 20:17 | . D. A receptor. It's from a PV. It's different in |
|
| 20:22 | sense that MK eight A one will the only one that's an M. |
|
| 20:27 | . A receptor is open. So that these protein channels are three dimensional |
|
| 20:35 | and they have these different crevices and acid sequences to each different elements can |
|
| 20:43 | in sort of like a key into lock. But then what happens is |
|
| 20:49 | once the channel opens this three dimensional changes its confirmation and all of a |
|
| 20:55 | new little crevices a new binding size you know assets are now open. |
|
| 21:03 | we also discussed this concept that if molecules are binding to the same |
|
| 21:09 | they're competing against each other, they're competitive agonists or they're called competitive |
|
| 21:15 | So obviously a Tv will bind to side than MK 801 because MK 21 |
|
| 21:22 | a channel to change its confirmation to open to find to find to bind |
|
| 21:26 | different sides. So um now item it's mentioned PCP um uh it's a |
|
| 21:44 | , it's a very strong narcotic street . And the reason why I mentioned |
|
| 21:49 | is because an M. D. . Receptor and many of these receptors |
|
| 21:53 | will talk about glutamate gaba receptor They have many elements and many drugs |
|
| 21:59 | combined to them and some of them safe pharmaceutical medications. Others may be |
|
| 22:06 | for nutraceutical preparation to thunder illicit street that are designed and engineered in the |
|
| 22:12 | that we don't know how they And mechanistic lee binding of uh PCP |
|
| 22:19 | crystal methane and NBA receptors can evoke and acute and potentially even chronic schizophrenia |
|
| 22:29 | a single or a couple of uses these drugs. And some of these |
|
| 22:34 | are very strong. People literally can their mind by single use of |
|
| 22:39 | So that's something to be aware of . The same molecules the same receptors |
|
| 22:46 | we always discuss. There's natural endogenous . There are chemicals that are uh |
|
| 22:54 | antagonists, there are chemicals that are and then there are chemicals that could |
|
| 23:00 | these systems. And those could potentially some of the illicit drugs that are |
|
| 23:04 | the streets. They are actually this shows. Do you remember voltage clamp |
|
| 23:10 | ? Yeah so voltage clamp recordings this the reversal of zeros and guess what |
|
| 23:17 | the zero and M. D. . Current reverses zero million volts and |
|
| 23:22 | reverses zero million volts. E. . S. P. S reverses |
|
| 23:26 | million volts and played potentials reverses zero volts all of these things reverses zero |
|
| 23:32 | volts now this is their reversal potential is a little bit different from the |
|
| 23:37 | potential because obviously equilibrium potential is for ion and in this case through ample |
|
| 23:44 | an NBA receptors you have flux is more than one ion, sodium and |
|
| 23:49 | and calcium. So this is now more to as reversal potential. The |
|
| 23:55 | reverses this potential into the opposite direction you can see but it's a reflection |
|
| 24:00 | multiple ionic species traversing through this and . D. A receptor channel now |
|
| 24:06 | it's not just a single ion with own equilibrium potential. So you cannot |
|
| 24:11 | this equilibrium potential. You can call reversal potential due the individual ionic currents |
|
| 24:20 | its equilibrium potential. Yes they That's why we can also call it |
|
| 24:24 | potential. But in this case this more than one species. It's not |
|
| 24:28 | potential reversal potential. This is this sort of a technical language for it |
|
| 24:34 | . And what this shows is that normal physiological concentrations of calcium which is |
|
| 24:40 | million moller on the outside of the . If you release glutamate at minus |
|
| 24:47 | you're recording an M. D. . Currents, you have voltage |
|
| 24:50 | you have pharmacology, you blocked ampara you can do whatever you want because |
|
| 24:56 | have a lot of techniques in hand clamp and so on. So at |
|
| 25:01 | 30 you start seeing some currents then reverse at zero and then you can |
|
| 25:06 | an M. D. A receptor actually conducting a lot when these de |
|
| 25:10 | positive potentials you can and now what if you remove magnesium you put zero |
|
| 25:18 | on the outside of the cell, release glutamate and an M. |
|
| 25:21 | A channel is open. And that this experiment proves that in normal physiological |
|
| 25:28 | and normal magnesium concentrations and M. . A receptor is blocked until it's |
|
| 25:33 | polarized. But if you remove magnesium you release little mate sure an |
|
| 25:40 | D. A receptor will be opening conducting through this. So this just |
|
| 25:44 | that magnesium blocks and then the reception magnesium can allow an M. |
|
| 25:51 | A receptor to open up more hyper potentials. Which is interesting right? |
|
| 25:56 | you would say well what if there a lack of magnesium in the |
|
| 26:00 | Does that mean that M. A receptor indeed would be more |
|
| 26:04 | So some of these ions that we're about and not only ions for creating |
|
| 26:11 | is but now this magnesium ion as plug blocks something. And the presence |
|
| 26:19 | that eye on the amount of that on $1.2 million dollars versus zero million |
|
| 26:25 | can affect the function of these very glutamate receptor channels. These are the |
|
| 26:35 | plots. So we looked at the plots for individual channels. These are |
|
| 26:41 | I. D. Plots or Angela channel. And this one the nonlinear |
|
| 26:49 | is for an M. D. receptor channel. And the way that |
|
| 26:53 | experiment is conducted I'm gonna sit down and if you don't mind is that |
|
| 26:58 | have a couple of things here that have to read. So first of |
|
| 27:03 | minus 80 minus 40 plus 20 is potential Vm. Why is it at |
|
| 27:09 | 40 or plus 20? Because you're it? You're using voltage clamp? |
|
| 27:15 | so what are we looking at We're looking at isolated currents. Okay |
|
| 27:20 | currents are inward currents. Right and inward currents. And then here it's |
|
| 27:25 | outward current. Remember that? All now we're gonna stimulate this this cell |
|
| 27:33 | gonna stimulate the cell. This is stimulation dock right here at different potentials |
|
| 27:39 | -80 -40 and plus 20. This is the same as we're gonna release |
|
| 27:45 | . We're stimulating the salad Glue to . Were either stimulating the glutamate fiber |
|
| 27:51 | we're releasing the glutamate with a pipette we're engaging glutamine around the cell. |
|
| 27:56 | we're stimulating the glue to me and measuring at two time points were measuring |
|
| 28:03 | just a couple of milliseconds following the which is the early current or the |
|
| 28:11 | measurement. And we are measuring another is 50 millisecond uh time bar here |
|
| 28:19 | 20 milliseconds later. This other dotted is measuring the late response. Okay |
|
| 28:26 | this is the early response. the audit line going across. And this |
|
| 28:30 | the late response. So you lock Salad -80 -100. Even -80 |
|
| 28:41 | And you measure this early current. know that this early current is ample |
|
| 28:47 | . Already told you that. And can check it with other things like |
|
| 28:53 | . So this is the early And as you measure this early current |
|
| 28:56 | can see that the non N. . D. A receptor zor ample |
|
| 29:00 | will have this linear I. Curve with the reversal potential at zero |
|
| 29:06 | volts. All right, everybody can that. Now when you're gonna do |
|
| 29:13 | same experiment minus 80 you're also going take the second measurement 20 milliseconds |
|
| 29:19 | The late measurement. And you're gonna that at minus 80. There's no |
|
| 29:24 | here. This is where all the . This is the current deflection. |
|
| 29:28 | there's barely any current of minus There is some current. All the |
|
| 29:33 | under blue curve is N. D. A. Current. So |
|
| 29:38 | can see that at minus 40. there's significant in M. D. |
|
| 29:41 | current and you can see that it even larger at minus 30. It's |
|
| 29:48 | larger. It's nonlinear. So these the circles it reverses its zero miller |
|
| 29:54 | and it conducts a lot. You see it actually prefers to conduct |
|
| 30:00 | And this is the late current which an M. D. A |
|
| 30:04 | And finally you apply your blocker in experiment, which is a PV. |
|
| 30:10 | that blocker specific to an M. . A channels. So if you |
|
| 30:14 | a blocker for an M. A channels, do you expect to |
|
| 30:18 | the entire E P. S. . Or the early component of E |
|
| 30:22 | . S. P. Or the component of E P. S. |
|
| 30:26 | . The late one because an D. A. Is responsible for |
|
| 30:29 | late component of E P. P. And so if you apply |
|
| 30:32 | PV, this blue area under the collapses into this first black line and |
|
| 30:40 | this first black line here which means block the late currency with a |
|
| 30:48 | And this uh measurement shows the open that in the presence of a P |
|
| 30:56 | . With the exception of some minor currents, the current is pretty much |
|
| 31:01 | . Remember this is current. V voltage. Okay, so by |
|
| 31:08 | with a P. D. You the late current. But the question |
|
| 31:12 | , do you affect the early current a PV? And the answer is |
|
| 31:17 | correct. And so this is the between the open triangles and close |
|
| 31:22 | which is no difference. It's a curve. It's not affected by late |
|
| 31:28 | blocker and M. D. A . A PV component blocker. So |
|
| 31:34 | you can maybe use the knowledge like said from previous lectures, I V |
|
| 31:39 | , equilibrium potential versus reversal potential linear versus nonlinear and M. D. |
|
| 31:47 | . I. V curve and specific in this case a PV which blocks |
|
| 31:53 | late component but does not affect the component. Professor why does um an |
|
| 32:02 | . B. A. Uh prefer more positive memory voltage an M. |
|
| 32:11 | . A. Because it's it needs remove magnesium and the more gets the |
|
| 32:16 | the more magnesium is leaving but then starts reversing because then potassium starts coming |
|
| 32:23 | and and and closing in on the the sodium coming out and closing in |
|
| 32:27 | sodium coming in. So very Okay so this is really cool when |
|
| 32:33 | talk about I think that maybe this lecture is going to be doing a |
|
| 32:37 | for maybe it was too ambitious to to finish this in half an |
|
| 32:41 | And the point is not to get the material but actually try to explain |
|
| 32:46 | and make sure everybody understands it This is a really interesting slide first |
|
| 32:52 | all within a gated channels calcium on ginny and cellular something mechanism cellular |
|
| 33:02 | So first of all, when we about calcium, permeability and ample |
|
| 33:06 | I said that only certain ample receptors permeable to calcium. It turns out |
|
| 33:12 | a single amino acid substitution, the . This experiment where you have |
|
| 33:19 | you apply glue to mate and the receptor glue are too which is an |
|
| 33:25 | receptor has the Q. In it is glutamine in this sequence here. |
|
| 33:31 | has a Q in M. Two is the second sub unit of that |
|
| 33:39 | and that complication of glutamate evoked sodium and above calcium currents. So there |
|
| 33:51 | some amFA receptor channels that are also to calcium. However in some instances |
|
| 33:59 | ample receptors have the glutamine exchange with which is our and now you apply |
|
| 34:12 | , you can still see significant sodium and there's no calcium current. That's |
|
| 34:20 | cool. And the analogy of it be that you came to the building |
|
| 34:28 | that building had an operating elevator And a huge building and it has five |
|
| 34:37 | that go up and down and you one brick from this building and all |
|
| 34:44 | a sudden two of the elevators stopped . This analogy basically tells you that |
|
| 34:53 | acids are the building blocks for these dimensional protein channel structures. Right? |
|
| 34:59 | have thousands of them. You removed . It's the same the same as |
|
| 35:04 | know, basically removing one chair and can sit in the room. Okay |
|
| 35:13 | that's that's that's pretty significant uh on ginny during the development. You only |
|
| 35:21 | an M. D. A receptor certain synopsis and the synopsis are referred |
|
| 35:26 | as silent synopsis because guess what if release glutamate on just an M. |
|
| 35:31 | . A receptor channel where's deep polarization there is no ample receptors. So |
|
| 35:40 | are instances of course where an D. A receptor will get |
|
| 35:43 | But for the most part the synopsis be silent and only later ample receptors |
|
| 35:48 | get expressed there and they will wake synopsis up. Okay so this is |
|
| 35:53 | early development, this is what And M. D. A receptors |
|
| 35:58 | their own subunits. Remember we talked these subunits 1234 alpha beta in this |
|
| 36:08 | you have NR two A. NR B. NR one subunit and energy |
|
| 36:13 | . And composition of these subunits can during the development. An analogy would |
|
| 36:20 | that one wall of the building changes as the as the brain develops and |
|
| 36:30 | composition basically of the building changes over developmental phases. Um There's cellular |
|
| 36:41 | activity dependence changes with age and And it says ample moves fast. |
|
| 36:48 | of course you have changes with age you have different expression of subunits, |
|
| 36:53 | expression of receptors. First an D. A. Than an |
|
| 36:56 | D. A. And AMP with N M. D. A. |
|
| 36:58 | its sub unit. If there is activity these processes will be engaged more |
|
| 37:05 | there's less activity these processes will be less. This will affect plasticity. |
|
| 37:11 | can affect the term that we use . T. E. Stand for |
|
| 37:15 | term plasticity which is basically the connectivity neuronal networks and the other thing that |
|
| 37:23 | we talked about fluid mosaic model of plasma membrane. I said some of |
|
| 37:28 | elements move fast. It was a membrane. So these elements trans membrane |
|
| 37:34 | receptor channels move really really fast and can move from extra synaptic spaces into |
|
| 37:41 | synaptic spaces. So there's a lot movement going on at the level of |
|
| 37:45 | plasma membrane. Can I ask a about the calcium? Yeah so this |
|
| 37:55 | was saying that when we have the glutamine amP a receptor that it conducts |
|
| 38:04 | if I'm reading it right. But on the slide we were saying AMFA |
|
| 38:09 | not conduct calcium only. Um And so some of them contain that are |
|
| 38:15 | some of them contain the Q. some of them will conduct but typically |
|
| 38:22 | we we we we we know that M. D. A receptor will |
|
| 38:27 | for sure calcium and only some ample will conduct it. Okay so this |
|
| 38:33 | also added that occurs naturally pretty Uh You also have this in in |
|
| 38:44 | book. Okay. Um if you to cross check it. Um Now |
|
| 38:52 | is just an example of Meadowbrook tropic receptor signaling and what we call a |
|
| 38:58 | of inter cellular pathways. So yes have a lot of metabolic tropical intimate |
|
| 39:04 | not just stamp on an M. . A. Which are which are |
|
| 39:07 | a tropic but binding off glutamate metabolic receptor can take this molecule P. |
|
| 39:16 | . P. Two and transform it fossil like a C. P. |
|
| 39:23 | . C. And P. C. Basically activation of PLC will |
|
| 39:30 | this P. I. P. into I. P. Three which |
|
| 39:34 | an arsenal triphosphate and into the A. G. Which is the |
|
| 39:39 | glycerol. And so now what you've is by activating this medical tropic |
|
| 39:45 | You broke down one molecule D. . P. Two which created two |
|
| 39:51 | pathways. One pathways membrane bound A. G. Which interacts with |
|
| 39:56 | molecule called P. K. Averting find A. C. And |
|
| 40:01 | I. P. Three. The arm of this pathway can target |
|
| 40:06 | P. Three receptors on smooth and plasmid particular um And binding of |
|
| 40:13 | P. 32 I. P. calcium receptor channels will allow for these |
|
| 40:20 | smooth and the plasmid particular and calcium to release calcium into the cytoplasmic |
|
| 40:27 | We call that calcium in the side plasma is very tightly controlled. There |
|
| 40:32 | no not much of free side of calcium just floating around there are peaks |
|
| 40:38 | those concentrations of calcium where you have synaptic active zones and more calcium comes |
|
| 40:45 | when voltage gated calcium channels open up it's not much of it floating around |
|
| 40:50 | side applies And because apart from being Duyvil and kati on it's also a |
|
| 40:57 | messenger. And so by having this of intracellular calcium source. This is |
|
| 41:06 | way in which medical tropical receptors increase calcium concentrations which can act interact with |
|
| 41:13 | molecules kindnesses and can interact as secondary in the cells, kindnesses again is |
|
| 41:23 | that will post quarrel it. So can add a P. 04 group |
|
| 41:31 | a neuron on a receptor channel let's okay this would be kindnesses and prospect |
|
| 41:46 | . Okay well defense for aly will this P. 04 group and there's |
|
| 41:59 | balance of these molecules inside the It's kind of an interesting regulation that |
|
| 42:03 | not very well understood but there is spatial specificity that I think emerging um |
|
| 42:11 | the cells that have these concentrations of and hospitals is that they have to |
|
| 42:17 | . Okay, Gaba Gaba A Gaba is different from Gaba B. Gaba |
|
| 42:31 | is uh on the tropic Gaba receptor ligand gated channel binding of Gaba will |
|
| 42:39 | for influx of chloride and Gaba A create an eye PSP. Right so |
|
| 42:48 | this pretend too much. So when is released and there is binding to |
|
| 43:03 | A receptor there's influx of chloride and up of negative charge which causes |
|
| 43:17 | P. S. D. Okay post synaptic potential post synaptic potential. |
|
| 43:25 | now look at all the other things combined to this reception a lot of |
|
| 43:34 | go to over the hump parties on some people wait until friday and when |
|
| 43:41 | do if they consume alcohol, ethanol bind to gather receptors and uh how |
|
| 43:53 | this happen? I mean you consume and gets into the blood. It |
|
| 43:58 | through blood brain barrier gets into the bonds to Gaba receptors and then you're |
|
| 44:06 | one drink. A lot of people com having one drink inhibition goes up |
|
| 44:12 | inhibited and then two months of ethanol cause disinhibition. So three or four |
|
| 44:19 | later. You know people taking off dancing on the table, That's disinhibition |
|
| 44:25 | . Right. Benzodiazepines, you may heard of benzos or benzodiazepine, very |
|
| 44:33 | anti epileptic drugs, epilepsy medications to seizures that will bind to Gaba |
|
| 44:41 | They're agonists. They will all open Gaba receptors. So it will open |
|
| 44:47 | until a certain point where it's no responsive with ethanol barbiturates or sedatives will |
|
| 44:56 | interact with gather receptors and anything that inhibition in a way increases inhibition |
|
| 45:03 | I. P. S. Is A is a sedative. Uh |
|
| 45:08 | steroids also have a binding site on Gaba A channel. This is Gaba |
|
| 45:15 | receptor channel and this is Gabby. is not like hey hey is I'm |
|
| 45:25 | tropic. So it's an entropic receptor . Gaba B is a metabolic trophic |
|
| 45:35 | channel. It's not a channel. you put in coupled receptor and it |
|
| 45:40 | two things activation of Gaba B will potassium channel but opening potassium channel through |
|
| 45:52 | B. This is our G protein . This is yeah it will be |
|
| 46:03 | B. That's yo Gabba Gabba and potassium channels and positive charge. Leaving |
|
| 46:14 | leaving is going to cause even further polarization. So the initial I. |
|
| 46:22 | . S. P. Is Gaba . That if the cells have metabolic |
|
| 46:28 | gaba B receptors the late phase of I. P. S. |
|
| 46:34 | Is going to be gabby. Why it late? Because remember that there |
|
| 46:41 | a delay, there is a delay activate g protein complex for that catalytic |
|
| 46:47 | to bind the potassium channel. Open channels. So you have a delay |
|
| 46:52 | 2030 40 50 milliseconds depending on the of these channels are closer to each |
|
| 46:58 | , number of these channels sensitivities and different sometimes. Okay what else can |
|
| 47:03 | do? Pre synaptic li it can calcium channel. So remember we looked |
|
| 47:09 | the mechanism of endocannabinoid that said it close calcium channel and regulate synaptic particular |
|
| 47:16 | . So God would be pre synaptic can do similar things in a way |
|
| 47:21 | a similar mechanism. So Gaba binding pre synaptic gap would be receptors can |
|
| 47:30 | or block voltage gated calcium channels. Gaba is chloride. Gaba B. |
|
| 47:38 | either influence the g protein complex potassium or calcium channels. Open potassium closed |
|
| 47:48 | awesome. Alright so let's look and if we can understand this mess |
|
| 47:55 | Uh uh I will not ask you on this diagram of the exam but |
|
| 48:02 | tell you what every lecture I tell that there is a diagram that if |
|
| 48:05 | take notes on it and you understand on that diagram and use it as |
|
| 48:11 | note taking gonna race the these notes your own notes. Rewrite these notes |
|
| 48:16 | your own way. You'll really understand lot of things that we've been talking |
|
| 48:21 | especially when it concerns glutamate ergic and ergic signaling. So let's look what's |
|
| 48:28 | on here you have in here is inhibitor salad or excited for yourself |
|
| 48:36 | Sound good. Glue them in here excitatory cell excitatory sound good. This |
|
| 48:43 | one neuron. We always said neurons receive both inhibitory and excitatory synopsis. |
|
| 48:49 | ? This guy receives a lot of . Okay and this Gaba binds to |
|
| 48:55 | A. And hyper polarizes the south influx. And it also binds to |
|
| 49:03 | B. And it hyper polarize is of the cells because of potassium have |
|
| 49:10 | lot of hyper polarization here because we Gaba and Gaba B. Then you |
|
| 49:15 | this initial I. P. P. Followed by the late phase |
|
| 49:19 | I. P. S. Turns out that when you have Gaba |
|
| 49:28 | also contain Gaba B receptors and that's second function. So if there is |
|
| 49:35 | over of this gaba back pre synaptic in ambient levels you don't need much |
|
| 49:43 | this release ambient levels. You can pre synaptic Gaba B. Which will |
|
| 49:51 | calcium and will regulate the secular push an optical, Does that ring |
|
| 49:59 | . Does that it's similar to CB receptors that can target they actually will |
|
| 50:04 | the same voltage gated calcium channels. always talked about how there are several |
|
| 50:10 | that can regulate things. So here can have Gaba other receptors because the |
|
| 50:18 | that releases gamma also has Gaba B is pre cinematically on itself as well |
|
| 50:24 | other receptors. All right. Or can also activate CB one receptor here |
|
| 50:32 | in the cannabinoid system and also regulate particular disease. Good. Now what's |
|
| 50:41 | on And glutamate synapses? Can you the camera so that we can see |
|
| 50:47 | going to the slide um Glutamate is is here. And you can see |
|
| 50:56 | glutamate will bind to glutamate receptor channels this case it's showing that it will |
|
| 51:05 | you no activation. It can cause of AMP A. And M. |
|
| 51:08 | . A. It can cause influx calcium through an M. D. |
|
| 51:12 | . Or through some of those ample to it looks a calcium can interact |
|
| 51:19 | calcium kindness too. And calcium chinese throw into cellular cascade can regulate potassium |
|
| 51:37 | and open potassium channels. So this G. Is also present in exhibit |
|
| 51:45 | announced. So you haven't this is inhibitor. This synopsis an excited but |
|
| 51:53 | also expresses gather B. So it's not an inhibitor scenario because it's gloomily |
|
| 52:01 | is being released but it contains the aspect here because you will hyper polarize |
|
| 52:09 | cells by opening potassium channel and the of glutamate and we don't make the |
|
| 52:13 | for signaling is to de polarize the . So Gaba B now is post |
|
| 52:20 | lee on the excitatory selves. And there's a lot of Gaba released in |
|
| 52:28 | inhibitors synapse and it spills over it got to be header receptors on excitatory |
|
| 52:36 | synaptic terminals and they can regulate calcium they can regulate the secular release. |
|
| 52:47 | right so this is all of the that we have. Post synaptic density |
|
| 52:58 | M. D. A. calcium channels potassium channels. Gabba, |
|
| 53:03 | B. This explains really well how and Gaba B functions. It explains |
|
| 53:09 | little bit about how glutamate functions but how Gabby can affect dramaturgical synopsis. |
|
| 53:14 | once again this pre synaptic control of and the secular releases reminiscent of the |
|
| 53:21 | cannabinoids that we've just spoken about at excitatory synopsis. So this is the |
|
| 53:31 | that I did when I was in school. Uh It was really cool |
|
| 53:36 | actually. I was able to isolate nerve from young uh mouse brains and |
|
| 53:45 | optic nerves were connected to the structure processes visual information. The thalamus and |
|
| 53:52 | was able to stimulate the nerves and the thalamus excitation. So it's very |
|
| 53:59 | because we talk about excitation and inhibition very typical that the cell that receives |
|
| 54:08 | inputs will receive inhibitor inputs. So you have a stimulation of the fibers |
|
| 54:17 | some of these fibers are excited to glued in eight fibers. And some |
|
| 54:23 | these fibers are inhibitory gaba fibers and shock these fibers with a stimulating electrode |
|
| 54:34 | you have both in the optic And then you record activity from the |
|
| 54:39 | synaptic cell. And you can see . P. S. P. |
|
| 54:44 | . That are followed by Gab A. I. P. |
|
| 54:47 | P. S. That are followed gaba B. I. P. |
|
| 54:51 | . P. S. So this A P. S. P. |
|
| 54:55 | is followed by Gaba A. That followed by Gaba B. This is |
|
| 55:01 | cool because you're about in distance about centimeter away from stimulation. It's really |
|
| 55:07 | actually most of the stimulation experiments are in much closer proximity here in one |
|
| 55:13 | not millimeters centimeters away. So we this response. And there are specific |
|
| 55:18 | by Q. Colon by colon. specifically block this this this this uh |
|
| 55:26 | this inhibition. So but we won't into the blockers. But the point |
|
| 55:31 | is that Gaba and Gaba B. won't talk about the antagonists. They'll |
|
| 55:36 | their own respective antagonists. But it's typical because neurons receive the excitatory inhibitory |
|
| 55:42 | that they'll have combinations of those P. S. P. |
|
| 55:45 | And I. P. S. . S. And it depends on |
|
| 55:49 | timing. If you activate excitation very to inhibition at about the same time |
|
| 55:54 | will likely cancel each other out. you activate a lot of excitation and |
|
| 55:59 | inhibition excitation will one and E. . S. P. S. |
|
| 56:04 | win if you activate a little bit excited to fibers. But a lot |
|
| 56:08 | inhibitory fibers inhibition will win and just will hyper polarized and stay hyper polarized |
|
| 56:15 | plant G protein coupled receptors are very structures there seven trans membrane uh alpha |
|
| 56:29 | hell exists, remember expanding alpha hell that are linked to do proteins and |
|
| 56:36 | acetylcholine will have a number of medical receptors. Glutamate will have a lot |
|
| 56:45 | medical tropical suckers. Their subtypes of B, Gaba B. R one |
|
| 56:49 | . Or two or three A. so on. Serotonin five HT one |
|
| 56:53 | two HD four or five different Dopamine norepinephrine alpha alpha two. We |
|
| 56:59 | about alpha two and beta munn descriptively one and Catelyn new delta opioid |
|
| 57:10 | Cannabinoid CB one CB two receptors are medical tropic receptors, 80 P. |
|
| 57:17 | Dennis and receptions. So the way teepee act is actually is different from |
|
| 57:25 | denison but denison will also block calcium person optically and stop glutamate release. |
|
| 57:32 | dennison is ubiquitously expressed an excited this and activation of G protein complex through |
|
| 57:39 | dennison receptor blockade of voltage gated calcium no glutamate release. You go to |
|
| 57:46 | when you drink caffeine, it blocks an antagonist to denison receptor which allows |
|
| 57:54 | the calcium channel to stay open and the glutamate release to take place. |
|
| 58:00 | so that's what caffeine encourages and promotes glutamate release and the wakefulness and |
|
| 58:09 | These are transmitter gated channel structures. can see that a lot of them |
|
| 58:14 | have these subunits and these subunits alpha . Gamma delta will have the trans |
|
| 58:21 | segments that are M one M M three M four trans membrane segments |
|
| 58:26 | four segments will make each one of subunits and there's just a lot of |
|
| 58:34 | in the structure and this variation in structure is a different subtype Gabba. |
|
| 58:42 | Gabba B one B two which is different function of the receptor chloride versus |
|
| 58:50 | versus slow versus fast and so So for civil Colin we have to |
|
| 58:58 | the agonist and antagonist for sid alkaline norepinephrine. You have to know the |
|
| 59:06 | and data to push pull mechanism for in eight you have to know AMP |
|
| 59:11 | and M. D. A. of A P. D. And |
|
| 59:13 | and Q. X. For your gaba and gaba chloride in a couple |
|
| 59:21 | potassium regulation, A. T. is P two X receptor, A |
|
| 59:26 | . P. And the A. receptor Dennis and receptors antagonists for this |
|
| 59:33 | or Dennis and receptor and caffeine is antagonist. And here comes the complication |
|
| 59:43 | you can have alpha beta gamma delta units and you can have different subtypes |
|
| 59:48 | those subunits 1234. And you can different combinations of the subtypes of the |
|
| 59:54 | units and that's where you get the of the whole receptor channel as a |
|
| 60:01 | in general the chemical signaling and chemical are amplifying, meaning that once the |
|
| 60:09 | is released it's not one it's difficult locked. That means a lot of |
|
| 60:15 | channels get activated. Each channel can multiple G protein complexes. Each protein |
|
| 60:22 | can activate multiple downstream substrates, generate neurotransmitters. Secondary molecule secondary messengers. |
|
| 60:32 | chinese can then affect several receptor channels channels, multi gated channels nearby. |
|
| 60:42 | an amplifying system as opposed to the junction system which reduces the amount of |
|
| 60:47 | that passes from cell to cell. signal that can actually multiply and amplify |
|
| 60:54 | response. So for amplification we have messenger cascades and you can have this |
|
| 61:02 | . We're talking about the transmitter combined receptor 123 and receptor subtype two can |
|
| 61:14 | amplify and activate three different systems. . Y and Z. You can |
|
| 61:21 | divergence where abc transmitters will buy into receptors and a convergence I'm sorry and |
|
| 61:30 | will all converge onto the same infection . Cyclic GMP through different receptors through |
|
| 61:39 | neurotransmitters, it's part of the redundancy you want to activate this effective |
|
| 61:44 | you have this redundancy. The transmitter through A two activates the factor 2 |
|
| 61:56 | and five. A. One receptor say can activate a factor three B |
|
| 62:03 | can also activate a factor three. if you lose one system of neuro |
|
| 62:09 | and one stop type of A one , you can still get to the |
|
| 62:13 | of three. This is a redundancy how you can get to the molecules |
|
| 62:19 | molecules and the factors inside the Okay. And so this actually concludes |
|
| 62:26 | was meant to be about half an to 40 minutes of lecture and I |
|
| 62:30 | see that it's one hour and seven of lecture. So the question I |
|
| 62:35 | for you, do you want to learning about C. N. |
|
| 62:38 | Today or do you want to stick all of this information on neuro transmission |
|
| 62:44 | try to reside it before the And then we will change the syllabus |
|
| 62:50 | and start the C. N. . On uh on monday. So |
|
| 62:55 | monday we do have a class, just have to log on for 10 |
|
| 62:59 | to take the quiz. So please to class. Uh if you can |
|
| 63:03 | take it during the class time you but you know, then come back |
|
| 63:08 | class. If you're online, you , you can take the quiz and |
|
| 63:11 | back to class, something like Um So I think I'll leave it |
|
| 63:18 | because there's quite a bit of there's quite a bit of knowledge that |
|
| 63:23 | gained on neural transmission. We started contrasting neuro muscular junction C. |
|
| 63:29 | S. Now you understand how complex cns signaling means you have glutamate gaba |
|
| 63:36 | acids. You have a means, , there's the means of different from |
|
| 63:41 | assets have different functions with each one them as a sub serving a different |
|
| 63:47 | , observing a different mental state or of being if you may and uh |
|
| 63:55 | understanding the signaling, excitatory inhibitory signaling how you create the E. |
|
| 64:00 | S. P. S and I PS. So uh if you look |
|
| 64:05 | the sample exam, I believe there's exam two, there might be some |
|
| 64:09 | questions that relate to the neuro transmission . And so this is what I |
|
| 64:14 | do is I would look at whatever of questions that have on that |
|
| 64:19 | about 20 or so that are dedicated neural transmission. This would be a |
|
| 64:24 | way to prepare yourself with the Another thing is I realized that there |
|
| 64:29 | some overlapping slides in the lectures. you could do yourself a favor and |
|
| 64:38 | reorganize the slides that help you study best. A couple of those slides |
|
| 64:44 | mis misplaced out of order. It's apologies for that. Um and |
|
| 64:50 | if you like I said, want use a couple of slides to summarize |
|
| 64:55 | notes and the key messages that we learning over the past three or four |
|
| 65:01 | and I would encourage you to do to write and then you will be |
|
| 65:06 | pretty much for the midterm too for section of midterm to you'll just have |
|
| 65:12 | review it from the term too because will learn more information on the brain |
|
| 65:18 | a little bit on the visual system . Okay. Any any questions so |
|
| 65:31 | and it should be I was told by the end of the day it |
|
| 65:36 | be showing up. If it is , I'm gonna email them but it |
|
| 65:40 | be there should be there. We be able to do it it before |
|
| 65:47 | . You can do it after The class is gonna start covering the |
|
| 65:54 | nervous system. So, I think have, you know, a few |
|
| 66:01 | now to review them with serial. right. Thank you very much |
|
| 66:14 | I will see you in class on and uh let's see what's on the |
|
| 66:22 | . Okay. Camera, I got on the quiz covering all the new |
|
| 66:28 | . After example. One lecture. . So, the these four |
|
| 66:32 | basically, and you're just missing 123 , you know, I had about |
|
| 66:40 | you having |
|
