| 00:02 | This is lecture three cellular neuroscience. will continue to talk about neurons and |
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| 00:08 | dramaturgical signaling. We ended last week about gendered experience and we talked about |
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| 00:19 | fact that normal development of connections, development uh precise structure and distribution of |
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| 00:29 | gendered experience is very important for normal and normal brain development in general. |
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| 00:39 | is giving me a bit of a . So I'm gonna stay in this |
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| 00:46 | And we talked about this image and said that neurons are very complex. |
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| 00:53 | their cellular anatomy is complex, their inputs are complex and they're multiple. |
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| 01:01 | be tens of thousands of times 100,000 inputs and the cell has to process |
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| 01:08 | information precisely. And the cell will a lot of glue dramaturgical excitatory synopsis |
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| 01:16 | excited to encompass a lot of gaba inhibitory synopsis. The excitation and inhibition |
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| 01:23 | to be balanced in order for the to function normally. If there is |
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| 01:27 | imbalance in these conditions, this can to neurological disorders. But if you |
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| 01:33 | improper connectivity and when we're born, mentioned that we have more synopsis when |
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| 01:40 | newborns and we have a lot of things that are non specifically interconnected with |
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| 01:45 | other. And then a lot of neuronal connectivity undergoes what we call anatomical |
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| 01:53 | and specifications where precise neuronal circuits reform on the activity. And there's pruning |
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| 02:02 | decrease in the number of the synapses pruning of the dendritic spines. Uh |
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| 02:08 | a condition that I started mentioning last fragile acts and I don't necessarily want |
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| 02:15 | go into great detail to this But this is where I actually |
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| 02:22 | well, what could be maybe a kind of a clinical overview the |
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| 02:29 | And this is where my google searches I do pub med leads me back |
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| 02:35 | pub med. And sometimes what google it accept the phrases, the things |
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| 02:41 | you search better than pub med that you to pub med articles. But |
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| 02:47 | X syndrome is also known as martin syndrome. It's a genetic disorder. |
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| 02:55 | , these are the features of It's inherited and it is severe intellectual |
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| 03:04 | and it's the most common mon a cause of autism spectrum disorders. |
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| 03:11 | fragile acts falls under autism spectrum Under that spectrum, there are multiple |
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| 03:22 | and disabilities and disorders have fallen under general umbrella of autism spectrum disorders. |
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| 03:33 | , there are certain what it talks is the Children that have this |
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| 03:39 | There are images that you can look online have these very elongated and narrow |
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| 03:46 | , very prominent big jaws. And just quoting basically this parliament description and |
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| 03:55 | article and basically some abnormal physical features , that can be recognized, such |
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| 04:04 | large errors and large testicles, uh apparent and older Children as you can |
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| 04:12 | a third of these Children have features autism of delayed speech hyperactivity and seizures |
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| 04:21 | very calm. So, when we about fragile X, that's a syndrome |
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| 04:28 | a disorder we haven't gotten to talk the FM RP. Or fragile X |
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| 04:34 | retardation program. But what we already mentioning is that these Children will have |
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| 04:43 | what we call comorbidities and the co is another disease that is associated in |
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| 05:00 | case with abnormal neuronal circuits, abnormal spine formation that leads to overall motor |
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| 05:10 | but also brain hyperactivity leading to seizures epilepsy in many cases. And epilepsy |
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| 05:18 | when you have repeated seizures, having seizure will not basically diagnosed with |
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| 05:28 | So this is related to this gene is M. F. FmR. |
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| 05:36 | or FMR one or F. R. P. The protein of |
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| 05:40 | gene is the p the fragile Mental retardation protein. FM RP. |
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| 05:55 | basically what it is is that if are missing this gene or if you |
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| 06:01 | a mutation in this gene, one the features that are observed is abnormal |
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| 06:10 | of these dendritic spines. So the on a cellular level that we're discussing |
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| 06:18 | abnormal dendritic spines and abnormal connectivity by same virtue in the brain. Because |
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| 06:26 | talking about seizures typically that means that is a balance of excitation and |
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| 06:32 | Typically too much excitation. Too much on the body hyperactivity hyperactivity in the |
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| 06:39 | means potentially seizures. So we're not get into treatment modes of fragile |
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| 06:52 | But if you do uh fragile And seizures, for example how common |
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| 07:00 | is, it will always hyperactivity of are common, You will see that |
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| 07:07 | increased risk of seizures. So these comorbidities and we will talk about epilepsy |
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| 07:13 | mechanisms of excitation and addition of balance the on the cellular level in this |
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| 07:19 | and some of the features. But is something that basically is pretty |
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| 07:27 | Uh And one of the most common mental recommendation on recommendations under autism spectrum |
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| 07:35 | . It affects both um males and but it seems to be less severe |
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| 07:43 | females and fragile X. There's a X side on the on the |
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| 07:52 | So some notes as they relate to image and the processing of the information |
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| 08:01 | excitation and condition the neurons communicate with other by virtue of releasing neurotransmitters. |
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| 08:11 | if this yellow neuron we call pre neuron that pre synaptic neuron has a |
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| 08:19 | input or other neuronal input. And it gets deep polarized enough and excited |
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| 08:24 | it will produce an action potential in axon initial segment, the closest one |
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| 08:30 | the selma. And that action potential be conducted down the axon. And |
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| 08:37 | action potential will get regenerated at each here in the myelin nation and it |
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| 08:46 | de polarize the external terminals and cause neurotransmitter release. So if it's excitatory |
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| 08:54 | solves. It will cause the release glutamate. If this is an inhibitory |
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| 08:58 | into neuron the action potential here will the release of Gaba and the post |
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| 09:06 | cells response will depend largely on the of the receptors of that post synaptic |
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| 09:11 | expressive now, neurons have to make decisions of integrating tens, hundreds and |
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| 09:22 | of synaptic inputs within a matter of . And that's why neurons are unique |
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| 09:27 | excitable tissues there the fastest ones muscular cardiac skeletal muscles that can produce action |
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| 09:36 | there much longer in duration. So slower. The processing in neurons is |
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| 09:43 | the fastest that we that we that can think of in the in the |
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| 09:50 | and many of you know that neurons an action potential. And today we're |
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| 09:56 | talk about some of the dynamics of action potential. So for example, |
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| 10:05 | my undergraduate course I get into the of what we call the equilibrium potentials |
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| 10:15 | nurses equation behind equilibrium potentials. And gonna leave out some of this information |
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| 10:22 | I may not test you on of in ernst equation as as we discuss |
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| 10:28 | particular diagram but with this particular diagram it has a lot of information that |
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| 10:34 | like for you to understand and uh able to know and ask any questions |
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| 10:43 | you have any questions, let's start the fact that Neurons addressed the resting |
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| 10:51 | potential which is our M. which stands for resting membrane potential is |
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| 10:57 | -65 -70 million. And when neurons this value here which stands for a |
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| 11:11 | threshold or action potential threshold. So the neuron potential of the membrane changes |
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| 11:19 | minus 72 approximately minus 45 million poles will produce an action potential. That |
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| 11:28 | all or none. The action potential produced via the influx of sodium and |
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| 11:39 | flux of potassium. And this is through ion channels. So last lecture |
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| 11:47 | put some notes and I said iron types these particular channels that we're talking |
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| 12:01 | , our sodium channels. And potassium . And these particular channels are gated |
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| 12:12 | voltage. So a lot of times will see N. A. And |
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| 12:19 | subscript of V. Okay subscript. V. And that V stands for |
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| 12:27 | that indicates that in the literature or the textbook or in the diagram you're |
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| 12:34 | at volt educated sodium channels, voltage potassium channels are voltage gated calcium |
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| 12:41 | Now what does it mean that they gated by voltage? And how do |
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| 12:51 | understand this? If we were to a diagram we went to draw, |
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| 13:11 | and we have a protium and this is actually an ion channel. So |
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| 13:22 | is abundance of sodium on the outside the cells and there's abundance of potassium |
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| 13:33 | the inside of the cells. sodium have to cross through N. |
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| 13:41 | D. And potassium ions have to through KV. That means that potassium |
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| 13:54 | to go to find potassium channel that's for potassium sodium is going to commend |
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| 14:02 | sodium channels that are selected through But we just talked about gates and |
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| 14:09 | does it mean that they're gated and does it mean that their voltage |
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| 14:14 | So let's talk a little bit about channel, sodium channel is as any |
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| 14:24 | channel is comprised of amino amino acid and a lot of these amino acid |
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| 14:34 | can have charges, negative charges, charges. And so both educated sodium |
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| 14:42 | actually have a little sensor inside of . And when there is a little |
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| 14:49 | of deep polarization on the inside, voltage sensor will slide up and as |
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| 14:56 | voltage sensor slides up, it will open up the channel. This channel |
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| 15:02 | typically closed with the gate right here nothing can pass through it. But |
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| 15:09 | there is some positive charge build up , this voltage sensor will cause a |
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| 15:15 | will change and will swing this gate so that the sodium ions can come |
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| 15:23 | and sodium coming inside will be responsible the rising phase of the action |
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| 15:31 | So the way that the sodium channels built is that as the census slides |
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| 15:38 | and the gate open sodium channel has second gate and this second game is |
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| 15:44 | activation gate. So the channel will from open two inactivated. So channel |
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| 16:02 | inactivated because this other ball and swing mechanism will close this this channel. |
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| 16:12 | , so the minute there is positive the sensor slides up, one gate |
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| 16:18 | . But because of that gate the second gate actually closes. So |
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| 16:23 | channels are open transcendently only for one two milliseconds. And that's why sodium |
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| 16:29 | also responsible for the initial phase of action potential for the rising phase of |
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| 16:34 | action potential. And this is how channels are gated by voltage with a |
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| 16:41 | sensor. And in order for this to reopen again, you actually have |
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| 16:47 | remove this gate and close the channel the channel will go from open to |
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| 16:56 | it to closed to back again into mode. Uh huh. So these |
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| 17:08 | the features of both educated sodium potassium both educated potassium channel does not |
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| 17:17 | two games. It only has one . It only has the activation |
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| 17:25 | And as soon as sodium channels start and they start closing uh during the |
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| 17:33 | phase of the action potential and at peak of the action potential all of |
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| 17:38 | sodium channels, most of the sodium have already closed. Then potassium channels |
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| 17:44 | up. And as potassium channels open this gate also opens potassium ions go |
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| 17:57 | . So there's the flux of potassium therefore potassium is responsible for the falling |
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| 18:04 | of the action potential. So these voltage gated channels. And these bolt |
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| 18:22 | channels, sodium and potassium voltage gated are responsible for generating the action |
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| 18:29 | Then at some point the membrane potential is V. M. Stands for |
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| 18:35 | number in potential number of potential VM find its way back to the minus |
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| 18:42 | million volt value. And part of is going to be done by N |
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| 18:47 | K pump and make a pump is pump that actually utilizes energy in the |
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| 18:53 | of a T. P. To these ions across their concentration gradient. |
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| 19:00 | a lot of sodium on the outside will keep putting more sodium on the |
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| 19:07 | , potassium on the inside but we putting more potassium on the inside. |
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| 19:14 | so this is voltage gated. be gated, podium channels. |
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| 19:25 | Them in addition to vis gate it all educated channels, we also have |
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| 19:37 | gaining. Okay. And these ligand channels, receptor proteins but they need |
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| 19:50 | binding for example of glutamate in order open and allow for the flux of |
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| 20:02 | inside and potassium to the outside of salary. So this is voltage |
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| 20:13 | This is ligand gated. When we about glutamate or gamma and gamma glutamate |
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| 20:22 | to receptor channel and the flux of , they need a chemical to bind |
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| 20:30 | agonist antagonist. We get into those in the in the maybe trouble down |
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| 20:36 | this lecture maybe next. So voltage channels ligand gated channels and there are |
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| 20:44 | other types of channels that are ligand are mechanically gated. So what |
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| 20:54 | what does that mean? That means there are channels that based on the |
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| 21:07 | mechanics. Okay, so mechanical Now these channels are responsive to touch |
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| 21:23 | pressure, actual physical displacement and the displacement ends up opening these channels. |
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| 21:34 | they're mechanically gating. There's nothing there's no chemical binding, there's an |
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| 21:42 | pressure. Okay then it sends us the membrane that has certain parts of |
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| 21:50 | protein that allows for this protein to a channel and open. So mechanical |
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| 21:56 | . We have voltage gated channels, have ligand gated channels and mechanically gated |
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| 22:03 | . And we also have ligand gated that are not channels that will talk |
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| 22:08 | lot about. And those are G coupled receptors. So there Ligon |
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| 22:23 | there's no gate. They're like independent . Those are trans membrane proteins that |
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| 22:42 | linked to G proteins complex to G complex that can influence nearby channels and |
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| 22:53 | flux of aisles through these channels. they need the binding of the Ligon |
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| 23:03 | order to activate the inter cellular signal the G protein coupled receptor And this |
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| 23:11 | protein complex and activate either other channels affect cell mechanisms inside the cell. |
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| 23:25 | Liggins gated can be channels and Ligon receptors also not channels but they can |
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| 23:34 | other channels and they can influence other processes. So this is all that |
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| 23:42 | would like for you to carry away the slide and to know for example |
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| 23:49 | voltage gated sodium channels have two gates they're very transient, very fast opening |
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| 23:56 | closing and then potassium channels up one , they don't open until the following |
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| 24:03 | of the action potential. So they're activated. Um And they're responsible for |
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| 24:10 | following phase of action potential. There's more information on the slide in |
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| 24:18 | when neuron membrane potential or VM. . Polarizes. That's because neuron is |
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| 24:25 | excitatory inputs, Ludin eight inputs. if it is hyper polarizing that means |
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| 24:32 | getting inhibitory inputs or the inhibitory synopsis being activated. So the more deep |
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| 24:40 | , the more excitation there is, more the membrane potential D. |
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| 24:44 | Is going to be driven to deep potentials, the more likely this neuron |
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| 24:48 | gonna want to fire. So if have too much glutamate and too little |
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| 24:54 | then it will constantly want. The can lead to abnormal synchronization of neuronal |
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| 24:59 | and seizures. And typically neurons don't that much. Even when they're engaged |
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| 25:07 | fire a few patterns of action And for the most part they're |
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| 25:11 | With the exception of one or two potentials here and there. Unless they're |
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| 25:17 | activated by direct and strong stimulus. other than that if you were just |
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| 25:23 | record from neurons there will be sparsely action potentials unless they have like I |
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| 25:29 | , a direct input of activity exciting we're doing or inhibiting they would be |
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| 25:35 | them, it would be completely It might be a little bit of |
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| 25:40 | side question. When you talk about , it's not firing. Is that |
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| 25:46 | same even for brain areas that on the time? I think the brain |
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| 25:50 | things have to monitor your breathing all . They're still very slow pattern just |
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| 25:55 | maybe that tissue doesn't need it Or I guess. No, that's |
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| 26:01 | that's a great question because there are parts of the brain that will be |
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| 26:07 | active and that will periodically produce these evicted it, then you're correct. |
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| 26:12 | it concerns the brain stem centers for , for heart trade, there is |
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| 26:18 | rhythmic constant activity that it is nonstop you want your heart to keep |
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| 26:24 | You want your your belongs to be and that signal what's constant that's coming |
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| 26:31 | . But if you were to, say polka brain and record a cortical |
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| 26:37 | and just say, oh, attached neuron and you're like, well, |
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| 26:41 | just fired a spyglass, You 20 seconds and then buy it or |
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| 26:46 | . I don't know what it So a lot of neuronal activity is |
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| 26:50 | and non synchronized and processing unless it to be jolted with input, get |
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| 26:57 | or it has abnormal synchrony which then in seizures and epilepsy. So there |
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| 27:06 | definitely what you're talking about. We those neuronal populations. Pattern generators. |
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| 27:15 | for brain stem neurons as a pattern . You have a constant pattern generator |
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| 27:23 | your heart to write the essay notes the atrial node constantly. Right. |
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| 27:30 | there's control of these centers and the also are in the same pattern or |
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| 27:35 | to the pattern for for breathing or rate. Mhm. Great question. |
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| 27:44 | And then there are certain parts of brain that are more repetitive and rhythmic |
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| 27:48 | certain loops that are more repetitive and like thalamus cortex. But then there |
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| 27:54 | a lot of distributed activity in the cortex that sometimes you're when you're doing |
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| 28:00 | E. G. Recording electroencephalogram you not pick up much activity for the |
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| 28:13 | that are engaged directly into the Uh How much of it? You |
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| 28:21 | ? It's also it's also a question going on here is being cut |
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| 28:29 | Yeah so these are beautiful images. you're seeing is a note of ranveer |
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| 28:37 | . And you see green is potassium 1.2. So you already know that's |
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| 28:44 | volt educated potassium channel 1.2. Okay. And Casper a protein that |
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| 28:54 | our paranormal junction between the Myelin ated cells and the axon. So I'm |
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| 29:04 | in green you have the sodium channel here and potassium channel is in |
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| 29:14 | But what it's telling you is that note of Ron veer and these are |
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| 29:20 | notes of Ranveer. These are the and the Myelin nation along the axon |
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| 29:26 | well as the axon initial segment. is both educated sodium channels here. |
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| 29:33 | initial segment in particular. They're loaded these both educated sodium and both educated |
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| 29:39 | channels And that's because each break in note of ranveer the action potential is |
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| 29:51 | . So the actual potential originates here axon initial segment and then in between |
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| 30:00 | break the nose of Ron beer before reaches the external terminal there could be |
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| 30:09 | of these segments. The action potential get regenerated and it gets regenerated because |
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| 30:17 | have high densities of these volt educated and potassium channels so it gets regenerated |
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| 30:26 | the external terminal. It's the same but when it started at the actual |
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| 30:33 | segment here so this is some labeling basically exposing the distribution of these |
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| 30:44 | And obviously why you would have them to produce or regenerate that action potential |
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| 30:53 | the action potential arrives in the external it causes the neurotransmitter release. So |
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| 31:03 | there is a pre synaptic terminal deep , what it does, it opens |
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| 31:10 | channel which is voltage gated calcium channel here Prison optically and the deep polarization |
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| 31:19 | opening of the vault educated calcium channel two necessary things in order for the |
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| 31:27 | that has no transmitted to fuse to plasma membrane and caused the release of |
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| 31:31 | neurotransmitter exercise. Oh sis So one not enough deep polarization if you don't |
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| 31:42 | calcium influx. If something is wrong vault educated calcium channels you're not going |
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| 31:49 | be able to release the neurotransmitter. . If you have both educated calcium |
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| 31:56 | but you can't de polarize, it's all terminal the action potential. They're |
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| 32:00 | going to open because they're voltage dependent channels, they're both educated. So |
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| 32:07 | channels are located uh and concentrated at pre synaptic terminals. And usually there's |
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| 32:15 | densities of these calcium channels very close where the vesicles are located that are |
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| 32:21 | with the neurotransmitters. The reason why need calcium is because the neurotransmitter of |
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| 32:28 | look like this. They're very This is a cartoon of all of |
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| 32:34 | different membrane associated to some of them some of them trans membrane proteins. |
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| 32:43 | it turns out that these proteins that on the vesicles here, simplified as |
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| 32:49 | secular sneer complex. And then trance near complex. This protein complex from |
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| 32:55 | vesicles has to link up with the complex on the membrane so that the |
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| 33:02 | membranes are both possible lipid bi layers vesicles confused with the membrane of the |
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| 33:12 | and cause the opening of the poor the exocet. Oh sis ! And |
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| 33:18 | exocet oh sis this piece of the gets pinched off buds off, gets |
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| 33:26 | beginning the pre synaptic terminal through the of endo psychosis and gets refilled with |
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| 33:34 | neurotransmitters again. So deep polarization is calcium influx to develop a gated calcium |
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| 33:43 | . Protein protein complex interactions are all steps in order for the classical fusion |
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| 33:50 | neurotransmitter release to take place, the major neurotransmitters. Excitatory neurotransmitter glutamate and |
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| 34:06 | inhibit their neurotransmitter Gaba that we find the brain, their amino assets. |
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| 34:13 | also have a third amino acid neurotransmitter . So glutamate is excitatory and gather |
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| 34:24 | inhibitory. The difference between glutamate and is just one acid group C. |
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| 34:33 | . H. And all of the that are inhibitory neurons that express Gaba |
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| 34:41 | also express with tom a casa deco list. So if you were to |
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| 34:49 | the tissue for like we talked about circuit and I said if you were |
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| 34:53 | stain the cells you'll see 10-20% of cells that are God positive or inhibitory |
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| 35:00 | . And then we talked about how do distinguish different subtypes of this inhibitory |
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| 35:05 | and that's what we talked about. morphology, cell specific markers, connectivity |
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| 35:10 | action potential patterns. So the major neurotransmitter is one reaction dicker box elation |
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| 35:22 | from major excitatory neurotransmitter license in the cord replaces Gaba as a major inhibitor |
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| 35:35 | . So in the spinal cord glycerine the major inhibitory neurotransmitter and not gabble |
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| 35:41 | everywhere in the cerebrum it's gaba in cerebral glycerine is actually a co factor |
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| 35:52 | excitatory glutamate signaling and we'll get into of these details in the second. |
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| 36:00 | so if we were to look in brain and we were to stay the |
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| 36:10 | grave man Gaba, you will see distributed expression of Gaba throughout the cortex |
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| 36:28 | cortical structure cerebellum brand stone. So is God staying here and there is |
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| 36:43 | of God expressing cells. Well billions a billion because if we have billions |
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| 36:50 | neurons 10 to 20% would be God cells. So maybe let's say one |
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| 36:57 | throughout the brain and then you'll have few billion uh glutamate positive cells. |
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| 37:17 | so they need a different color. well we'll get around this is glutamate |
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| 37:25 | glutamate expressing cells will also be everywhere . You see seeing any one of |
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| 37:33 | sticks across access everywhere everywhere everywhere, is amino acid and then you're talking |
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| 37:41 | glycerine, you'll have lice in the cord and you little made all over |
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| 37:46 | spinal cord, everywhere, everywhere In addition to the Amino assets which |
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| 37:58 | from day one described and my analogy glutamate is positive or on switch. |
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| 38:06 | is inhibitory or off switch and there's in between and our neuronal activity, |
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| 38:15 | can be quiet, they can be active, they can be partially |
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| 38:18 | they can go through different patterns and activity is not only influenced by these |
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| 38:25 | acid neurotransmitters but they're also implemented by mean neuro modulators with this with the |
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| 38:35 | of acetylcholine which is one of the I mean neurotransmitters in the brain. |
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| 38:44 | of the artists are Tony and cata means are only going to act through |
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| 38:48 | protein coupled with suffers acetylcholine actually has ligand gated ion channels that it combined |
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| 38:58 | and G protein coupled receptors serotonin. it's energetic like molecules include trip to |
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| 39:10 | five hydroxy tryptophan and five hydroxy trip me. True serotonin and that would |
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| 39:18 | your five H. T. Okay, which is the five hydroxy |
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| 39:26 | 10 mean cata cola mean classes of modulators include tyrus em di hydroxy phenylalanine |
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| 39:37 | dopa dopamine, norepinephrine and epinephrine. a lot of these molecules have their |
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| 39:52 | distinct functions and a lot of these you can start viewing them as responsible |
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| 39:57 | different controls of that on and off switch. So norepinephrine and epinephrine or |
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| 40:07 | , it's sort of like adrenaline of brain. Hey Trip to fan and |
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| 40:16 | HTP is sort of a like commerce the brain but also affecting of the |
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| 40:22 | affecting of the appetite. Sexual interactions dominated by certain energy systems too |
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| 40:34 | Again, it's like when you associate about dopamine or dopamine ergic, you're |
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| 40:39 | about alert, engaged activity nor adrenal the brain fight or flight response. |
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| 40:51 | each chemical has it sort of its color that is related to different behaviors |
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| 40:59 | how it can influence the excitation and . Now the unique feature of these |
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| 41:08 | and I will have to go back the first uh session here. The |
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| 41:19 | feature of these molecules we already discussed that they're only expressed in a subset |
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| 41:33 | cells. So unlike these amino acid that have wide patterns of expression throughout |
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| 41:45 | . The norepinephrine is only expressed in cyril ius, these projections these arrows |
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| 41:54 | come out of local civilians are all that distribute themselves very widely and release |
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| 42:03 | norepinephrine and throughout the cortex and sub into the cerebellum and enter the spinal |
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| 42:11 | . The same with serotonin. Central will be Raffy nuclei and then these |
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| 42:18 | nuclei and green are supplying serotonin into cord into the periphery. Acetylcholine will |
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| 42:27 | have just a couple of nuclei in brain. So I think we had |
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| 42:32 | discussion maybe last semester somebody looked I said how many of these cells |
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| 42:38 | you have and turns out that you have hundreds of thousands of these neurons |
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| 42:44 | . So you may have hundreds of of these amino acid producing neurons. |
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| 42:49 | contrast to potentially billions of these amino girls. Uh I'd like for you |
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| 43:00 | think about this conceptually too light switch and off excitation and inhibition but it's |
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| 43:08 | robust, it's very global. It's throughout and then you have this localized |
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| 43:16 | and introduction of different behaviors and different all almost by these different uh you're |
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| 43:25 | modulators that control your light switch. you have a dimmer, you have |
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| 43:32 | and things that I analogize with that a light switch. Yes, but |
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| 43:44 | I don't like dopamine and like be or some other place. So what |
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| 43:48 | like. What does that mean that made from dopamine that comes elsewhere. |
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| 43:54 | of just like travels to the Cornelius and then that's where the that |
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| 43:59 | it into. Yes. If the would have that enzyme they can convert |
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| 44:04 | into into another neuro modulator. You're . And a lot of times they |
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| 44:10 | be located next to each other because can see these are brainstem nuclei |
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| 44:16 | And what you're getting at is that of them is a precursor to |
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| 44:21 | Right? And you're correct. So there will be uh synthesized using the |
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| 44:29 | . And if the cell has an that can convert the dopa into into |
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| 44:37 | or norepinephrine and two different. So diagram I hope that answers your |
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| 44:45 | At least in part if the cell amino acid dicker box Alice it can |
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| 44:56 | dopamine. But if it doesn't and has tyrosine hydroxy Alice it will make |
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| 45:04 | and different Souths adjacent will have different to process these precursor molecules um into |
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| 45:19 | know the next the next molecule. just generally speaking, like you expected |
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| 45:29 | , might be a button with the ways inside of that area. |
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| 45:34 | absolutely. If it is making if talking about norepinephrine exactly, you'll be |
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| 45:39 | to stay in in fact the cells reveal the whole nucleus by using the |
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| 45:46 | B hydroxy stain. Yes. And some of some of these things |
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| 45:52 | some of the exchange of chemicals is we're trying to reveal they may have |
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| 45:59 | . but if you don't have an , then, you know, it's |
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| 46:04 | it's not turning into another molecule and don't if you don't have a |
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| 46:09 | you also don't react to that other . So we're still I think is |
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| 46:14 | modern nurse scientists trying to solve a of like especially like chemical exchange between |
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| 46:21 | , it's not just communication of releasing , but it's also seems to be |
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| 46:25 | exchange. And if you have another to synthesize and then you pass it |
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| 46:29 | to something else. So actually talked a friend of mine and colleagues from |
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| 46:37 | , Doctor chris Della, I'm gonna him, he's a very busy |
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| 46:41 | But once we get through this we , maybe another lecture I would like |
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| 46:46 | have him on for 15 minutes on zoom. He discovered a new mechanism |
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| 46:52 | which we talked to neurons last year published a pretty groundbreaking paper. So |
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| 46:59 | could uh maybe I could of course . Uh do me a favor and |
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| 47:04 | 15 minutes of this time. Just of like what do you think? |
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| 47:07 | start degree, what do you think is going on? Because he's constantly |
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| 47:12 | about things that are not textbook things that that are going forward looking with |
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| 47:20 | , great questions. But yeah, can see certain organization of these |
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| 47:25 | So they share the precursors, they the enzymes and then they're widely |
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| 47:30 | Now you can ask me what the , what is this pattern of wide |
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| 47:34 | and people will say it's like a system. What do sprinklers do |
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| 47:40 | Right. Is it really specific now kind of a move a little bit |
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| 47:44 | ? So and then so what does mean? So it's almost like para |
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| 47:50 | signaling that's coming from this neurons and means that it has some specificity sprinkles |
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| 47:56 | but then the response is going to just if the neurons will have the |
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| 48:00 | somatic receptors to what is being sprinkled other stuff may get you know metabolized |
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| 48:07 | cleared up and cleaned off. So , very good. Keep thinking about |
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| 48:15 | . And so this is one of types of the exchanges that we're talking |
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| 48:19 | . This is really a better representation the tri apartheid synapse and the exchange |
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| 48:24 | glutamate in the sense that neurons pre neurons that have the ability to turn |
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| 48:33 | glutamine to glutamate and they also release glutamate from the vesicles. And once |
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| 48:41 | glutamate gets released it will target glutamate . Some of them are ligand gated |
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| 48:47 | channels. Some of them are ligand g protein coupled receptors and that glutamate |
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| 48:52 | have its own transport or pre synaptic neuronal transporter. G. Lm. |
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| 48:59 | so whatever glutamate is unused here and fact glutamate once it gets released it |
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| 49:06 | to the receptors boston optically and then gets sucked back up into the pre |
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| 49:12 | terminals it gets reloaded into the vesicles gets ready for subsequent release again. |
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| 49:19 | that's not them in the story. cells on the right here you have |
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| 49:25 | , glial cells have their own O. G. Which is glial |
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| 49:33 | transporters. And this glial glutamate transporters suck up glutamate into glia they have |
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| 49:43 | taste so they will convert it into Jelen and then they will allow and |
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| 49:55 | some of this glutamine back to And neurons can. Now with Tommy's |
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| 50:02 | more glutamate and load up the So this shows that glia is very |
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| 50:10 | involved. You're saying that if we're that the way to neurons communicate with |
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| 50:17 | other through this neural transmission and glia in part regulating how much of that |
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| 50:26 | is available. So if you have dysfunction in glued in eight glial transporter |
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| 50:37 | let's say the dysfunction is transporter is working, it's not sucking out glutamate |
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| 50:41 | the synapse. You can have a where there's too much glutamate in the |
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| 50:45 | and has nothing to do with neurons neuronal signaling has to do with the |
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| 50:50 | that leah is not clearing enough glutamate there's too much of it and you |
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| 50:55 | hyper excitation and hyperactivity in the brain could be the opposite. The transporter |
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| 51:04 | to open, it's too active and time we release glutamate and just keep |
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| 51:11 | it all out of the synapse and not enough excitation. So that's lesser |
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| 51:18 | a case that you would see. more common to have an impairment and |
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| 51:23 | transporters that are associated with neurological disorders impairment of not being able to clear |
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| 51:31 | properly to transport things in this case . So we come back to this |
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| 51:39 | synapse again, leo will have a of different functions but they definitely, |
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| 51:47 | with astra sides are involved in synaptic control and even in the early synaptic |
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| 51:54 | or the formation of the synopsis because control them out of excitatory neurotransmitter |
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| 52:00 | They're intricately involved in how strong this and qualifications is. Communication Can be |
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| 52:08 | two neurons. Right? This is transporters, their co transporters of |
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| 52:21 | So it's not unique to the fact if you release glutamate it also gets |
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| 52:27 | transported back into pre synaptic terminal. same will happen with gabba. And |
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| 52:32 | you see, glutamate is not only transporters back into the synaptic terminal. |
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| 52:37 | also have to have exchange of glutamate exchange of gabba into the vesicles and |
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| 52:44 | is typically done by using the high gradient. There's a lot of H |
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| 52:52 | that gets loaded up into the vesicles gets exchanged for gaba or glutamate molecules |
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| 52:59 | sort of like a secular co transporters a way that are driven by the |
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| 53:07 | gradient. Okay. And next we're start addressing and talking about glutamate ergic |
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| 53:19 | and the types of glutamate ergic signaling we're gonna get into more details about |
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| 53:26 | nomenclature of glutamate receptors, structure binding of these glutamate receptors, things like |
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| 53:34 | , antagonists and the neural modulators. I'm a little bit short of time |
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| 53:41 | I keep looking at my watch because have to uh picked up my daughter |
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| 53:48 | 45 minutes on the other side of . So I will end a few |
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| 53:53 | earlier today if you guys if you're with this but just introduce this is |
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| 54:03 | will signal through Ambon MD and kinase and neurons those receptors. Glutamate is |
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| 54:12 | natural neurotransmitter or endogenous neurotransmitter agonist. an endogenous neurotransmitter and when it binds |
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| 54:23 | amP and receptors it will open those the same as with these molecules shown |
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| 54:33 | blue AMP A. And M. . N. Cain. Those are |
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| 54:38 | they're not endogenous their exogenous their chemical and each one of them is a |
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| 54:46 | different chemical that will activate specifically AMP receptor or an M. D. |
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| 54:54 | receptor. What kind of reception and three of these are what we call |
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| 55:03 | gated ion channels All three of them they have different features and the biggest |
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| 55:17 | between these channels typically ample and kind good group together based on their kinetics |
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| 55:28 | based on their conductance properties and D. A. Is different and |
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| 55:32 | distinguished because when glutamate binds to non . M. D. A |
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| 55:38 | So none of them D. R. Ample and teammate when glutamate |
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| 55:43 | to non NMDA receptors. That's all receptor needs. That's all ample receptor |
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| 55:50 | is glutamate was released and bound and starts conducting sodium and potassium and causing |
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| 55:56 | polarization personality. Excitation personality. But not the case with an M. |
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| 56:03 | . A. And M. A. Receptor actually has a magnesium |
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| 56:08 | is blocking it on the inside. is a magnesium pour that it combined |
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| 56:15 | and this magnesium is sitting and blocking M. D. A receptor |
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| 56:20 | So when glutamate is released and glutamate stein and M. D. A |
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| 56:27 | that's not enough to open an D. A receptor. It actually |
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| 56:32 | glycerine and this is a tricky I said the glycerin is the inhibitor |
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| 56:38 | a transmitter in the spinal cord. is a co factor for an |
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| 56:43 | D. A receptors in the cns the cerebrum and lie scene is shown |
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| 56:50 | this little license molecule er co factor binding together with glutamate is still not |
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| 56:57 | to open the reception. But what to happen is you need to get |
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| 57:02 | of magnesium and the only way to rid of magnesium is to cause the |
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| 57:08 | deep polarization through non NMDA receptors. once you have glutamate release ample is |
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| 57:17 | sodium comes in that deep polarization now kick out magnesium block and will allow |
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| 57:25 | an M. D. A receptor . So a lot of times an |
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| 57:30 | . D. A receptor is referred as coincidence detector because it has two |
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| 57:36 | detect pre synaptic neurotransmitter release and it two posts in optically detect deep polarization |
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| 57:46 | this magnesium to leave the channel Alright so now they're both Ligon gated |
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| 57:59 | channels but there are also glutamate receptors are G protein coupled receptors that are |
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| 58:07 | gated by likens. The ligand binding this glutamate receptor will activate G protein |
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| 58:14 | and they are not channels. This what we call metabolic tropic and metabolic |
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| 58:23 | signaling. And this is I on tropic receptor channels because they allow for |
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| 58:30 | flux of ions through them. So on the tropic. So when we |
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| 58:37 | back on monday we will get into details of the medical tropic versus iron |
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| 58:47 | tropic and delve into this glutamate receptors talk about more about glee and glutamate |
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| 58:55 | and all of these interesting things And a couple of articles and the lecture |
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| 59:02 | that I will be referring to. those figures that I'm showing two. |
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| 59:07 | the articles and I'll open and remind of them. I also did not |
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| 59:15 | the links from today's description of fragile syndrome but it's pretty simple and I |
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| 59:22 | upload that as a as a link an item so that you can recall |
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| 59:27 | of the key features that we talked fragile likes. Okay. All right |
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| 59:34 | thank you for being here. It's beautiful, lovely, windy and paul |
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| 59:41 | , and I'll see everyone on on |
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