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00:01 this is mid term to review for and Synaptic transmission communication of 100 billion

00:11 in the brain trillions of sin You lay out the brain and the

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

00:23 These guys know Ramon e Cajal uh Charles Sherington, Camelia gold, you

00:29 course from the past and below. who discovered neural transmission Siegel Colin by

00:35 vagus cranial nerve 10 that goes onto cardiac muscle and causes the slowing of

00:42 heart rate and he reapplied the fluid the naive heart and charlotte. Saw

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

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

01:00 a flux of ions and small molecules could secondary messages between the cells and

01:06 . You have chemical and electrical neural in the synopsis. You have access

01:14 accident, accident, sonic and gender ready we discussed that acts tectonics in

01:20 . You don't really affect how the the cell's integrative properties but it actually

01:26 the output properties of the cell where others analysis. Actually somatic an accident

01:32 , they affect how the cell is to integrate that information whether it's going

01:36 produce an action potential, distinguish between anatomy of typical excitatory around vesicles symmetrical

01:44 inhibit their symmetrical number and differentiations with vesicles here, we talked about that

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

01:57 . We talked about how the release acetylcholine will activate. Only nicotine acetylcholine

02:03 is different from the cardiac muscle. a skeletal muscle will activate and open

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

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

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

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

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

02:42 because of the employee potential or P. P. Being 70 million

02:46 in size or larger. So review neurotransmitter criteria. You have to synthesize

02:53 enzymes that degrade them and then you to have a whole system plus sin

02:57 binding the iron a tropic in The tropic receptor assistance. We'll come

03:04 to this one but review this that need deep polarization calcium entry for the

03:13 . Oh sis. And this whole of endo acidosis as well. Um

03:25 is in the synapses in the sea ask there's full and partial fusion.

03:31 you should review that uh in the Colin signaling. We talked about the

03:38 butcher line um and botulinum toxins that interfere with this particular protein complex binding

03:47 the member and protein complex and therefore the civil Colin release. Uh So

03:53 is prison attic person athletically you have effect from Taiwan East cobra and organophosphates

04:02 have their effect within the synapses effective a steel coal industries. So fast

04:09 transmission in the brain is mediated in cNS, primarily by glutamate and excited

04:15 arpa synaptic potentials. But the single activation of a single synapse would result

04:22 a very small deep polarization, about million volts on the half a

04:27 Also as opposed to the neuro muscular 70 million volts one synapse here is

04:32 million. So you need to have different active synapses and continuous neurotransmitter,

04:37 neurotransmitter release in order to reach the for the action potential generation. Uh

04:46 is mediated by Gaba and binding of gabba A channels or cause an influx

04:53 fluoride and I. P. P. N. I.

04:55 S. P. S. A synapses are also approximately 0.5 million volt

05:01 polarization. Have I. On a versus a memorable tropic signaling. I

05:06 tropic is when the wagon the molecule Colin agonist binds to a receptor and

05:15 receptor is a channel. And metabolic is when that receptor is not a

05:21 but it has been linked to ju and it can affect nearby ionic channels

05:27 through membrane attached or not membrane attached messenger cascades inside the cells you will

05:35 responsible for a single Colin synthesis. when the seal cohen Coley in chats

05:42 colima settle transfers. There's a ch till column is loaded up in the

05:48 released in the CMS. You have , a tropical single color receptors in

05:53 metadata, tropical single color receptors. they will be different. The function

05:58 different and this is different from the muscle and this is different from the

06:02 muscle but in particular in the skeletal you only have nicotine in K

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

06:13 we have glutamate synopsis which are excited gavel synopsis which inhibitor but a ch

06:19 nicotine nick acetylcholine receptors will cause deep and through mascara nick or metal tropic

06:27 receptors will cause hyper polarization in the cell. Once a seal Colin is

06:32 , it gets broken down by acidic unnecessary succeeded caster mccollum gets transported back

06:37 sodium and chatted back into pseudo And we discussed that medications for Alzheimer's

06:42 targeted local investor racers by blocking the of acetylcholine aster is a pseudo cooling

06:49 blocking um That's the local investor There is an increase in the civil

06:56 signaling. And so we discussed that alzheimer's medication this is a system,

07:01 system that has appeared early on in court, taxes a little cooling

07:08 Okay, so organophosphates will also do same thing if you're this is the

07:15 , it can masquerade nick. They their own agonist nicotine in Muscatine.

07:18 had their own antagonist career in Can we check the questions really

07:25 If I can open it? It's letting me so I'll get back to

07:33 second. We reviewed that the same of principles exists for cattle colony.

07:38 so we reviewed that uh dopa and and then later norepinephrine and epinephrine come

07:44 tyrosine. Um And we discussed in detail norepinephrine actually and signaling through europe

07:51 africa uh and came back and talked amino acid in your transmission again how

08:01 of the sounds that are inhibitory cells contain britannicus and deeper box Alice.

08:06 if you declare boxing it or you the C. O. H.

08:10 , this is Citigroup away you basically glutamate produced gabba. So it's one

08:15 reaction away. The major excitatory cns into major inhibitory neurotransmitter. We talked

08:24 about serotonin and how antidepressant medications and medications can control. Also the re

08:33 of these molecules just a breakdown in synaptic club but also re uptake of

08:37 molecules and how each one of these systems serotonin or cata cola means and

08:45 . They're involved in different functions. moods, appetite, sleep learning control

08:51 so on. And then we talked in the cannabinoids for under cannabinoids.

08:55 discussed that there is two major endocannabinoid A tour and and to r.

09:00 . Donnelley and Glycerol and with deep significant deep polarization and both inhibitor and

09:07 synopsis you can have increased production. synthesis of endocannabinoid with the influx of

09:15 and other cannabinoids are not stored in vesicles. Like all of these southern

09:19 york transmitters were just discussing. Instead used freely through plasma membrane and retrograde

09:24 . The target CB one receptors that located pre synaptic Lee and these are

09:30 couple receptors. So this metal tropic one receptors will actually regulate calcium channels

09:35 will close this calcium channels and regulate release of excitatory and inhibitory neurotransmitters so

09:42 they can harmonize through this negative feedback the pre synaptic side and through a

09:47 bit tropic signaling control the excitatory glutamate inhibitory gaba room. He's balancing excitation

09:55 inhibition in the brain and delta nine or delta nine tetrahydrocannabinol also actually receive

10:02 on receptors primarily in the brain. there is also another subtype of receptors

10:07 CB two. Cannabinoid receptor two in brain primarily expressed and we have dominated

10:14 in the body and the spleen organs are associated with immune function and immune

10:20 interrogates signaling is the release of neurotransmitter pre synaptic, post synaptic retrograde signaling

10:26 that neurotransmitter traveling from post synaptic side binding to pre synaptic receptors. This

10:32 also true for the gasses nitrous oxide carbon monoxide that act in the same

10:38 . There are also numbering soluble not in vesicles and have their pre synaptic

10:43 oxide Carbon monoxide target receptors to identify cells. We use these techniques,

10:50 history chemistry in situ hybridization and caging neurotransmitters as well as another technique that

10:57 discussed that was. And caging of neurotransmitters and the neurotransmitter mimic re which

11:05 shown here. Of course. For spatial summation, neurons can have

11:12 summation. So several synapses active at same time will submit that signal.

11:17 that signal from $0.5 million from one can become 1.5 million volt. And

11:23 you have 40 50 active excited tourist , it can reach now the ps

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

11:33 . If you do dumper all summation means a high frequency discharge of the

11:38 actual potential pie spike. Again you get a much larger mps B but

11:45 reach the same altitude as it does the spatial summation. That's because there's

11:49 slight delay if you're activating the same and time, there's time delay here

11:55 allows for the cps be to start polarizing rather than immediate response From spatially

12:02 three synopsis that are activated at the time. And unlike in axons that

12:08 this action potential and reproduce it and salty Tory conduction where each note of

12:15 that there is a break out of action potential and is the same uplifted

12:20 the axon initial segment. Ah And acts on terminal And the synapse.

12:28 not the case with dendritic cables. cable is not Meilen eight. It's

12:34 not fully insulated. So that means current is going to escape. And

12:38 we talked about this Lamb. The or the length constant and length constant

12:45 essentially if you inject the current which your 100% the zero value here at

12:53 injection, 100% current. And then place electrodes a long list and cable

12:58 measure how does this current decay of distance. And where does this

13:05 Over distance reach 37% of its That by definition is the voltage.

13:15 value. The λ and λ stands the length constant. So how far

13:24 this dendrite the signal is going to before it reaches 37% value is the

13:31 constant. So if for some reason have a lot of channels open and

13:37 you haven't done really cable that has high densities of channels. This lambda

13:44 Shorter, reaching 37% value here. if you have a longer length

13:50 that means that signal from its maximum will travel a longer distance here before

13:56 reaches its 37% value of video. this is synaptic integration and then for

14:05 and for inhibitory responses if you have synapse, it's not enough. 0.5

14:11 volts 40 million balls may not be because you have inhibition. If there

14:15 no inhibition you have excitation and you from the soma most of that or

14:22 of that signal from that synapses going reach the soma. But if you

14:29 inhibition along the way then you need have a lot more excitation. Because

14:33 you activate inhibition not only hyper polarizes cells but it also shunts the currents

14:39 of this dendritic cable and by shunting currents out at the level of the

14:46 the inhumane get no deep polarization no at all. So modulation when we

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

15:02 sideways potentially cycling KMp protein kindnesses. we'll come back to a different diagram

15:07 we talk about this again these are neurotransmitter assistance that we discussed. And

15:12 we talk about dad's neural transmission glutamate gaba of course they have. I

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

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

15:32 through metaphor tropic signaling. And so is different because they are also expressed

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

15:45 pharmacology of versatile colon and the sigmoid on the metal but tropic side when

15:51 activate a single colon was koranic receptor actually open potassium channel. So when

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

16:04 medical tropic must complement receptor you have cheap protein couple protein, a reaction

16:10 actually opens potassium channel potassium leaving will polarized. The sound. Glutamate is

16:19 much uh important to realize that glia all in glutamate signaling and glutamate

16:26 Again, you'll have that iona tropic metabolic. Tropical little interceptors had a

16:32 means movement, mood, attention and function dopamine. So dopamine disorder would

16:38 associated with Parkinson's disease, attention, function, adrenaline of the brain,

16:47 control serotonin also mood. So they overlapping functions as neurotransmitters definitely. But

16:54 can see that they do sub they're kind of a distinct functions in

17:00 brain. For the norepinephrine. What looked at is this push pull

17:06 this classical push pull system where two tropic receptors, if you have an

17:12 Colin, you have nicotine acetylcholine receptor in opposite way too meta tropic masculinity

17:19 receptor then here you have to some of metal tropic receptors. One is

17:29 receptor, another one is alpha two , norepinephrine binding to beta receptor stimulates

17:36 production of cycle game be through a sightly stimulation and stimulates the production of

17:42 kinase assay and protein kindnesses for late and can open channels and keep them

17:48 and in nearby the same molecule norepinephrine activate alpha two receptor causing an inhibition

17:56 the identical cyclists and decrease incitement campaign decrease in protein kindness production. So

18:04 have this one is pushing production of like mp important kind say another one

18:09 pulling away from producing more of These systems that we discussed like norepinephrine

18:16 serotonin or even other systems. So you have a subtle Colin system here

18:21 we discussed some greater life. See cooling system you see in green.

18:27 are the nuclei in the C. . S where you will find a

18:31 moe's that produces silk Colin and nowhere . So if you look at this

18:41 , so this is the magno cellular for brain produces acetylcholine and particular Pantene

18:48 ladder and also took mental nuclei produces Colleen. What does that mean that

18:55 act songs or seal Colin. Is going to be found in these two

19:00 . No, because this diagram in streets is better just like for a

19:07 goal in the same as the case snore and offering the same as the

19:11 for certain and they have very specific in the brainstem that express these

19:17 So the song was of these cells producers. It'll calling that produce more

19:22 now from the producer Tony and they in these very distinct areas in the

19:27 stem. But the projections out of nuclear the selma's the axons have these

19:34 that's all. Most of these massive that come out and project everywhere.

19:38 cortical e neo cortical and to serve element into the spinal cord. That's

19:44 they're referred to as module a torrey . To because they specifically uh synthesizing

19:51 nuclei uh the actor G protein coupled and glutamate and Gaba. The amino

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

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

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

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

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

20:28 . This process of under cannabinoid Where deep polarization. If you have

20:33 lot of deep polarization, what other do is they suppress the release of

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

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

20:53 polarization induced suppression of excitation or dsc acids neurotransmitters. Again, they will

21:02 their own transporters for glue to Dramaturgical neuro pharmacology. You have glutamate

21:09 will buy into three subtypes of receptors are distinguished based on their chemical agonists

21:14 antagonists, Tampa and MD and kind they also have different pharmacology so they're

21:23 by different agonists and blocked by different have different kinetics when glutamate is released

21:29 will immediately open ample channels, sodium uh flux skin causing the initial deep

21:37 . And only when magnesium block is through deep polarization than MD. A

21:43 will open and cause a significant influx sodium and calcium. The kinetics of

21:49 how fast or slow ample is responsible the early PSP component and M.

21:54 . A. For the late All of them MD A channels are

22:00 to sodium calcium and potassium and only I'm for channels are permeable to calcium

22:07 conductance from conductance perspective than India channels much larger conductors. 50 PICO seamans

22:14 also have their own distinct antagonist, key name is blocked by seeing

22:19 X. And an M. A receptor sites are blocked by a

22:24 . Because and I'm the areas after to detect glutamate. It also actually

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

22:35 deep polarization person ethically so it has have the pre synaptic component and passed

22:40 at the deep polarization because of that referred to as coincident sector. It's

22:45 detective pre synaptic and possible objectivity and not to be confused that NMDA receptor

22:51 a metal tropic with um interception because NMDA receptors just blocked by magnesium.

22:56 is not do protean couple. So India is responsible for the late portion

23:01 the PSP and has a slower kinetics you can see that there's many other

23:07 uh such as PCP and even zinc has binding sites on an M.

23:11 . A receptor. In this example discuss that if you use a voltage

23:16 and you record currents, glutamate induced and you block ampara receptors. What

23:23 see is a normal physiological at $1.2 -60 million volts. You barely see

23:31 opening of the channels. You have de polarize the member and potential to

23:35 30 to start seeing the opening of channels at zero million volts. It's

23:40 reversal for an M. D. receptor. It's an equilibrium potential for

23:44 M. D. A receptor positive you can see more significant current.

23:49 it's rectifying awkwardly produces actually and prefers conduct current awkwardly. But this is

23:55 physiological really because most of the South live in this dynamic Range of -80

24:04 -30 mil levels in normal conditions. if you remove magnesium from the solution

24:11 you use the same voltage clamp and release glutamate and you have ample blocked

24:15 you're recording an MD occurrence, you see the opening of an MD.

24:18 channels and this proves that if you magnesium blog glutamate we'll activate an NBA

24:25 . So in the absence of magnesium decrease of magnesium and India channels are

24:29 to be a lot more responsive to . They're going to be open and

24:34 magnesium condition can cause massive hyper excitability the brains leading to seizures actually.

24:42 apps too much excitation. Too much domain causing really made toxicity potential.

24:49 two I. D. Plots that discussed where for the fast Tampa early

24:55 and late slow an MD. A . So if you voltage clamped at

25:00 80 and you stimulate glutamate with this is and then you take a measurement

25:06 how much current there is minus For the early component you will see

25:12 emperor receptors show triangles have a linear . V. Plot. Um and

25:18 reversal at zero million balls. And you measure this lake current and the

25:24 of late current you will see that -80 million balls. This would be

25:27 circles here that are filled circles. filled circles Are showing that at -80

25:35 , 70. You don't have much the current compared to the and put

25:39 -60 and so on. Only at minus 40 or so in India current

25:46 significant. It's non linear versus zero and it is rectifying in this outward

25:55 . Of course the positive charge flow the outward direction. So if you

25:59 an M. D. A current which is a PV and it

26:05 The fact that early component, what do is you take an early measurement

26:09 one of these is early component with P. V. In it.

26:15 early component without a PV in It doesn't change anything about the early

26:19 . This A PV is a specific of an M. D.

26:22 Current. And if you measure a current in the presence of a PV

26:27 will see are these open circles and open circles is near flat line here

26:33 you that there is no late current because you blocked it and there is

26:40 more current that you would see. so the late current the NMDA currents

26:45 the PSB is illustrated here in blue and this is the blue current that

26:50 be blocked in the presence of a . And would produce this open circle

26:57 . I hope that explained a few that were there earlier. This is

27:02 interesting talk about switching Q. R . Yes, for glutamine, arginine

27:11 no single amino acid substitution can influence the hamper channel is permeable to calcium

27:17 early stages. Only an M. . A receptor is expressed or what

27:21 call a silent synapses And then there's subunit shifts in M. D.

27:26 receptor is called the development or Tajani uh dramaturgical signaling in India receptors and

27:33 silence and absence because nothing is going be polarized plasma membrane in the absence

27:38 ampara it's only an NBA receptors that affected, expressed at the very early

27:44 and then later ample receptors come into . There is of course changes with

27:49 and activity, ample receptors can move and out of the synapses in the

27:53 way there's significant plasticity. LDP Test for long term plasticity that is

27:59 by the odometer GIC nmd and Amber's for metal to tropic glutamate. We

28:06 . This is really important pathway that you activate metal tropical glutamate receptors you

28:12 P. I. P two through ibc into membrane bond So glycerol which

28:18 influence the protein kinase C. And divergence of this pathway into production of

28:23 nostril triphosphate and activation of the P. Three receptor on the smooth

28:30 the plasma, particularly inducing an inter calcium release. For calcium is not

28:35 an ion but also a secondary Gaba. Ergic transmission. Gaba binding

28:42 A receptor in particular will cause the of chloride and inhibition or hyper polarization

28:51 of activity in the brain. So of Gabba increases in tradition or dampens

28:57 in the brain. It's also aside ethanol, benzodiazepine and barbiturate nurse steroid

29:04 Gaba A receptors and Gabby receptors Gaba receptors uh when you bind Gabba to

29:12 chloride influx is gotta be receptors they tied through g protein complex to

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

29:26 potassium influx. So we discussed this synapse here and this is just in

29:35 putting everything together. You can have glutamate synapse and if you have significant

29:39 of calcium you can activate calcium kinds . And Gaba B receptors are located

29:48 prison optically and pasin optically. So receptors prison optically will block calcium influx

29:55 control neurotransmitter release is simulated in a to The CB one receptor function and

30:03 an optical Gabby receptors can open potassium and cause hyper polarization. So Gabba

30:12 , if this gaba synapses that are here inhibitory synapses through Gaba receptor a

30:19 that will cause influx of chloride causing early I PSP inhibitory boston after potential

30:25 the late hyper polarization through opening of potassium channels through the gabba. Be

30:31 , tropic activation and prison optically. this ambient gaba travels over here it

30:38 block further gabble release. So you an auto receptor regulation and if you

30:43 a lot of gabba that spills over an adjacent excitatory synapse. It can

30:48 control the release of glutamate by activated synaptic gaba receptors on the grid And

30:55 synopsis. Um So you can see that this very intricate interactions here between

31:04 A. Yeah baby receptors, potassium channels and an M. D.

31:08 receptor. Is this is a great questions for labeling diagram or identification for

31:14 exam. This is an example again if you stimulate synopsis that have excited

31:20 input. So this is a stimulus will first produce E. P.

31:23 . P. And if the synopsis flying to surrounded or innovated by inhibitory

31:30 . Boom Gaba A will inhibit the . P. S. P.

31:34 an influx of chloride trying to drive number of potential to the reversal potential

31:39 fluoride which is 1 70 million balls by the activation of the Gaba b

31:44 and opening of the potassium channel And flux of the potassium trying to reach

31:50 potassium including potential of -19 million walls grab a beer uh through gabby activation

31:57 opening of the potassium channels. And you if you block Gaba a receptor

32:05 is bike succulent. If you block gabba a response and you have in

32:11 and two it's exact same stimulus. you can see that if you have

32:16 excitation is followed by inhibition. Kind controls and checks excitation inhibition. And

32:23 you don't, if you block Gabbeh Baekje column you can see this massive

32:30 de polarizing plateau potential that you can in the cells. So a little

32:35 about the structure of the G protein receptors is seven trans member and spanning

32:43 analysis and a variety of different mineral receptor signaling from Seattle Colleen Gaba,

32:51 dopamine norepinephrine couple of cannabinoids https https only just the energy molecule and also

32:58 to dentists and receptors. And we also the caffeine too Dennis and recep

33:06 . Uh Yeah Dennis and acceptance as . Uh This is transmitted gated channel

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

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

33:28 four trans member incitement. Someone threw for what is notable here is different

33:35 of these subunits that cause a variety subtypes of gaba and Gaba B

33:41 And some of the interesting things is , nick must clinic or stuff.

33:44 afternoon nicotine Mascarenas, agonist, cura pena's antagonists. Um you have to

33:51 I am from India of course uh the gabba gabba G. And you

33:55 know by curriculum is the antagonist of a alpha I'm sorry 80 P.

34:03 denison receptors. A type dennison is agonist would discuss that a TPS and

34:08 agonist for different type of denison receptor P two X receptor But it's still

34:15 the dentist and receptor because they 80 stands for a dentist and triphosphate.

34:22 there you have caffeine as an antagonist a denison. So you have these

34:30 that are dentists in is caffeine. it does is uh increases glutamate signaling

34:37 a dentist and dampens glutamate signaling. in the evening time a dentist and

34:42 go up and dampen glutamate release and activity quieted down and let it ambition

34:51 more active and caffeine does the it increases glutamate released through a dentist

34:57 receptors through g protein coupled system. is the amplification that you can see

35:03 also different uh divergence, convergence, , parallel streams that you would see

35:09 this Nero chemical signaling and after our discussions in your transmission and you already

35:17 a quiz on this, there will more questions on the exam and there's

35:23 lot of good labeling questions that is to come from the cns and as

35:28 said, I'm not going to do a review of the Cns because we

35:33 finished talking about it in the last of days. But I would be

35:37 to take any questions you may And other than that, I'm gonna

35:43 it here with the recording today. luck on your

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