all right everybody Welcome to the beginning of module two we finished out module one talking about action potentials receptors consequences of the action potential and in this lecture the beginning of module two we're going to focus more on synapses themselves synaptic transmission and synaptic plasticity so let's recap really quickly um we've mostly been talking so far about what are called chemical synapses and we talked about two different types of receptors at chemical chemical synapses go ahead pause the video take a moment and see if you remember what those two types of receptors that we talked about are the names for them so we talked about like and gated ion channels or ionotropic receptors and G protein coupled receptors or metabotropic receptors okay those are two types of chemical synapses today we're going to talk about electrical synapses which is another type of synapse we didn't discuss yet and then we're going to spend a little bit more time on the chemical synapses but this time focused on um how neurotransmitter is removed from the synapse and how synapses can change in response to experience and contribute to what we refer to as neuroplasticity how synaptic plasticity underlies learning so as a bit of review here we said generally generally communication at a synapse occurs in one direction from a presynaptic neuron to a postsynaptic neuron that's called anterograde communication we say generally because retrograde communication does exist as well in special circumstances and we're going to see a little little bit about an example of retrograde communication at the very towards the end of this lecture today we've uh we've got an example of a synapse here between Neuron a and neuron B and it's sending its axon with its terminal region to the dendrites of another neuron so that would be an axodendritic synapse most common type in the CNS and uh yeah as we said this here this image on the lower right this would be an example of a chemical synapse okay we've got a synaptic cleft we can see vesicles neurotransmitter being released and we might imagine there's receptors here and here they look like little holes on this but these are receptors all right that's a chemical synapse what is an electrical synapse though well in electrical synapse another name for it is a gap Junction Gap Junction the name may seem kind of counterintuitive to you because you know what do you mean electrical synapse uh is it just shooting electricity across it kind of yeah uh an electrical synapse or a gap Junction is formed by uh two pores which form kind of like a tunnel or a tube it actually it makes me think of like the green tubes in in Super Mario that you go down it forms a tunnel between the membrane of two cells okay and so they're interconnected and they form what's called this Gap Junction and so the Gap Junction is connecting one cell to another and through this ions and other small molecules but mostly ions can flow directly in a bi-directional manner through the Gap Junction from one cell to another Well ions are charged electrically charged either negatively or positively right and so if you're able to just shoot a bunch of positive ions from one cell into another you are moving an electrical charge directly in that way so we call them electrical synapses they're very fast very small two to four nanometers remember our chemical synapses are more like 20 to 40 nanometers so these are about a tenth of that size very small and they're made up of special proteins okay which are called connexins connections each connection there are six which form a connects on so six subunits one two three four five six of them form a single subunit or I'm sorry format connects on six connections to a connexon that forms one half of the channel and then on the other side the other part of the channel you have it again six connections forming a connects on so two connect Sons together form that that single tube connecting to the membranes of two neurons okay these are interesting in terms of the study of um developmental uh issues congenital deafness things of that nature I believe congenital blindness you can see some of their Gap Junctions are found uh in many different places throughout the body but they are a very quick form of signaling in fact they're the fastest form of signaling in the nervous system right because it's super quick to just shoot ions back and forth between the membranes that said they're really fast but they're also very simple they can only do two things right they can either send depolarizing current by sending positively charged ions or they can send hyper polarizing current by sending negatively charged ions right compare that to our chemical synapses that can send messages to things like metabotropic receptors that have long-term changes in the Machinery of the cell much more complicated messages so you have very quick very simple messages which can be sent this way and they're called electrical synapses let's take a look here at what this looks like in terms of location so here is our plasma membrane first say Neuron a plasma membrane for neuron B we've got an intracellular space and then we've got an area where they're bumping up against each other and we've got these connections forming that pore that Gap Junction electrical synapse some places that you might find Gap Junctions uh you might find them between an astrocyte and a neuron where it's able to send molecules maybe nutrient molecules back and forth that way you might find them between an oligodendrocyte and neuron again sending different nutrients Etc maybe lipids involved in wrapping the sheathing and then most commonly you'll find them between neurons so one neuron is connected to another neuron this way and there's plenty of places that these can be these are just a couple examples there are inhibitory Gap Junctions in the cortex and the hippocampus which is involved in coordinating metacognition right higher end thinking memory and decision making and believe me there's a whole lot of chemical synapses involved in that too far more chemical synapses involved in those processes but there are some elect electricals as well and sometimes you'll see them in pyramidal neurons in the cortex as well where they're contributing small portions of of action potential voltages well around 10 percent so there are also such things as mixed synapses in which you've got a neuron which is communicating a pre-synaptic neuron communicating via chemical synapse to neuron B say Neuron a to neuron B and Neuron a and neuron B also have an electrical synapse between them too let's talk about a third type of synapse uh this special so we've talked about chemical synapses electrical synapses and now this third one this third one is a type of chemical synapse technically but it's special because it it's only involved in one type of area of the body and that's the neuromuscular Junction the neuromuscular Junction so nmjs are found in the periphery all throughout the body and they're formed where a motor neuron here what we call an alpha motor neuron sends its axon to a muscle cell to a muscle cell and it sends its axon there and it sends a particular neurotransmitter called acetylcholine abbreviated as ACH acetylcholine so this motor neuron its nerve connects to a muscle cell and it releases acetylcholine onto it and that synapse of motor neuron to muscle cell is called the neuromuscular Junction and acetylcholine is the primary neurotransmitter we'll see there's certain types of receptor there involved there as well so when acetylcholine is released at the neuromuscular Junction it causes muscles to contract it does it causes an action potential in the muscle cell which causes it to contract we're going to talk about later in the course at the end of the course we're going to go into detail on how that happens but this process is called excitation contraction coupling we'll come back to the neuromuscular Junction a little bit later in this lecture because I want to talk about the special receptor that's at the neuromuscular Junction what type of receptor it is how the muscular contractions are terminated but first we want to talk about another form of information Transmission in the brain so we've talked about chemical synapses electrical synapses a few different types of chemical synapses and now finally the last type of inform well one of the last types of information transmission that's going to be relevant to this course is called volume transmission within the brain we're going to see later we know that there's you know veins transporting blood around but there's also cerebrospinal fluid we mentioned this earlier in module one it's a clear fluid which contains ions and nutrients and it's flowing around the brain and the spinal cord and it flows through these various aqueducts and tubing that run through the brain which are called ventricles there are lateral ventricles here there is a fourth ventricle here and a third ventricle and this allows the movement of cerebrospinal fluid throughout the internal aspects of the brain and spinal cord and again it's carrying ions it's carrying nutrients lots of different things but the other thing that it can carry along are neurotransmitters let's take a look and see how that works here is our brain and you can see you can imagine basically that let's think back to uh the chemical synapse right you've got that space between the cells 20 to 40 nanometers presynaptic neuron it releases maybe glutamate onto the postsynaptic neuron and I use the the metaphor of pin pinballs being released to you earlier and I said hey it's like a bunch of pinballs are getting released by neuron the presynaptic neuron and some of them fall into the holes on the postsynaptic neuron which would be like The receptors but there's only so many receptors and then you've still got pinballs bouncing around what happens to the rest of the pinballs okay well Transporters take some up and auto receptor might bind some as well and then that kind of takes care of a lot of the pinballs but believe it or not it is possible for some of the pinballs your neurotransmitter in this example to escape the synaptic cleft okay not a lot but small amounts they might escape and get taken up by the flow of cerebrospinal fluid flowing around the brain kind of like the Lazy River if you've ever been to like wet and wild or any of those other theme parks they kind of get swept up by the current and carried along carried along so if we look at this image here this is actually a mouse brain but it's it doesn't really matter for our purposes you can see these various currents of CSF flowing around the brain and this is how neurotransmitter is being released from an area say like the arcuate nucleus of the hypothalamus you know they might get taken up by the current and flow along and Float until they bind a receptor that they fit in somewhere else randomly maybe over here in the hind brain maybe in the medulla okay maybe somewhere else maybe in the frontal cortex right maybe in the midbrain so volume transmission is a very slow process it's the slowest form of neurotransmission and it's a non-deliberate process meaning that it there is no intentionality to it um it's unpredictable right sometimes neurotransmitters get escape the cleft and get taken up by The Lazy River of the CSF and they float along until they randomly bump into something that they fit in okay so it takes very little energy it's a low energy cost system but it's slow and uh the efficacy of it the safety efficacy well is rather low in the sense that you can't really predict what's going to happen but we know very little about volume transmission and frankly it's unlikely that volume transmission occurs by random mistake right there might really be a reason some areas are more prone to their neurotransmitters getting taken up by volume transmission than others and there may well be a reason for this but we just don't know the answer yet so we we haven't quite gotten to that point uh so it's it's something that's relatively new When I Was An undergraduate studying Neuroscience nobody talked about volume transmission nobody knew what that was this is really something in the last 10 years or so that's that's been taken up in terms of prevalence and learning about what it does so in comparison again just to review in comparison to Classic synaptic transmission chemical or electrical volume transmission is very slow and take a moment now uh pause the video and ask yourself okay if I've got three different types of synaptic transmission chemical electrical volume how would you rank order those in terms of speed so I'll give the answer now the rank ordering would be electrical synapses are the fastest chemical synapses are the next fastest but there's two subtypes right there's ionotropic and metabotropic ionotropic are the fastest of the chemicals and chemical synapses and metabotropic are the slowest of the chemical synapses and then volume transmission is the slowest form of synaptic transmission of all or of neurotransmission of all we should say all right let's talk about neurotransmitters a little bit we are going to talk about neurotransmitters in much more detail also how they relate to drugs and behavior in a later lecture but right now we're going to just break them down into some basic categories and we'll talk about some basic common neurotransmitters there are three of the most basic common categories this doesn't mean this is everything okay but this is some of the most common we have our amino acid neurotransmitters and these neurotransmitters the amino acids they're the most simple form of neurotransmitter molecules and indeed they're the most abundant in the brain glutamate is your primary excitatory neurotransmitter and guess what it's the most common neurotransmitter in the brain and then you've got Glycine and Gaba Glycine and Gaba Gaba is probably the second most common neurotransmitter in the brain and it is the primary inhibitory neurotransmitter glycine is also inhibitory it primarily works at the level of the spinal cord whereas glutamate and Gaba are much more brain Centric so those are amino acids okay simple simple chemical composition and if you haven't had biochemistry or something like that yet don't panic I don't want you to get lost here don't worry about this right side of the figure and thinking oh boy I don't understand the organic chemistry of all this okay we're not worried about that in this course just know what the amino acid neurotransmitters are what some examples are next are the amines okay the amines and you can tell because they all I guess with the exception of glycine which is amino acid they have that INE suffix on them some of most of them m-i-n-e okay uh so some examples here would be uh dopamine acetylcholine uh and histamine so these uh tend to be involved in more complicated types of signaling a lot of the amine neurotransmitters are involved with g-protein-coupled receptors and that's not to say that you know that can't be happening with other types but amongst the amines is one of the more common places that you find g-protein-coupled receptors dopamine for instance is all g-protein-coupled receptors serotonin for instance all G protein coupled receptors acetylcholine has an ionotropic receptor and a g-protein-coupled receptor histamine lots of G protein coupled receptors there Etc so they tend to be involved in more complex aspects of con cognition in some cases uh and uh and long-term changes in the Machinery of the cell finally our third category are peptides neuropeptides these are the largest in terms of their size they're these long chains of amino acids well I guess the example says short amino acid chains but regardless they're chains of amino acids okay so they're bigger than than the other neurotransmitters okay some examples here dinorphine encephalin endorphins uh endorphins are your body's own endogenous that's what Endo in the beginning endogenous form of morpheme that's what that's why they're named that because they're endogenous painkillers they're involved in other things too uh but they're these big peptide molecules and they are involved in some more complicated uh signaling aspects too we'll talk about that more in the drugs and Behavior Uh information to later in the course here's a table you do not have to memorize this table guys uh I'm not going to ask you name name me all the peptides name me all the amines this is just for your purposes for reference right now just to give you a little to orient you to where we're going eventually okay this is just summing up a lot of what I've already said let's talk about neurotransmitter synthesis now we've already talked about neurotransmitter release at a out of synapse okay how neurotransmitter is released from the terminal end and uh you know we talked about the snare complex snap to tagman calcium exocytosis right but how is the neurotransmitter actively synthesized in the terminal end of the neuron and packaged into vesicles okay well there are two things going on in this picture here two of them and they're demonstrating two different things uh what we're seeing here is that peptides peptides undergo a different process of synthesis than amines and amino acids do let's start with the peptides if we follow this picture here peptides utilize a precursor which is stored at the level of the endoplasmic reticulum at the Soma of the cell okay so it starts at the level of the Soma where the endoplasmic reticulum is a precursor peptide is released from there and it moves to the Golgi apparatus and it combines with the active peptide there precursor active it synthesizes together and boom it makes a neuropeptide it is then released by the Golgi apparatus into what's called a secretory granule the Golgi apparatus releases it into a secretory granule and it travels down the length of the axon until it gets to the terminal end and it just floats around in that granule much like the vesicles we talked about earlier to a weight release so that's neuropeptides neuropeptides involve a precursor peptide at the level of the endoplasmic reticulum it gets released over to the Golgi apparatus where it's combined into an active neuropeptide and then it buds off of the Golgi apparatus in the form of a secretory granule travels the axon and gets to the terminal end now let's talk about amino acids and amines they are synthesized right at the end of the in the terminal Bhutan okay they're not synthesized in the Soma they are synthesized right at their point of release okay so they're synthesized uh by enzymes here you have a precursor molecule and an enzyme which Cleaves it into certain components and it combines and forms a neurotransmitter so you you cleave up some things and then you combine those parts into a neurotransmitter it's then stored in a synaptic vesicle by transporter proteins so enzymes cut up a bunch of molecules and then they are put together by Transporters and stored in synaptic vesicles don't remember though these Transporters are not the same Transporters that we talked about on the membrane okay they're slightly different the Transporters on the membrane bring neurotransmitter back into the cell after it's been released and then they send it back to the vesicles to be repackaged so then the vesicles float around in here and they await release they await an action potential and they awake calcium Etc to to help them fuse with the membrane and be released thank you uh these next couple slides I'm gonna I'm gonna skip through them because their review from module one okay this is just reminding you how it is that neurotransmitter is released from the presynaptic neuron to the postsynaptic okay we've got vesicles in this image we've got our snare complex we've got our calcium and it's helping it fuse with the membrane if you want a better tighter review on that go back and review um the previous lecture in this course from module one the last part of the action action potential part two here it is again snare complex synaptotagment calcium Etc fusing with the membrane out they go so given that we already covered membrane fusion and neurotransmitter release in module one what we're going to talk about now is neurotransmitter re-uptake re-uptake so we already talked about Transporters in the previous uh lecture we said they act kind of like vacuums you know they clean up the leftover neurotransmitter in the synapse bring it back to the cell where it can be recycled repackaged into vesicles how does it actually get back into the cell though you know the Transporters kind of suck it up and bring it to the membrane and say hold it there kind of like holding cattle in a holding pen up against the membrane but how does it actually get back into the cell so it gets released from the cell by a process we said it was called exocytosis it's exiting the cell it gets brought back into the cell by a process called endocytosis bringing it into the cell and there's a couple of different players here technically the whole process is called clathrin-mediated endocytosis and it involves a particular cast of proteins here what we see is dynamine or dynamine dynamin okay dynamin is a gtpace which helps to pinch off the portion of membrane so let's imagine okay let's let's take this okay we've got neuro let's let's start from the beginning we've got neurotransmitter it's released by exocytosis into the synaptic cleft okay and now here's a transporter let's imagine and it says okay I need to clean this up let's bring it back bring it back it sucks it up toward the membrane like a like a holding pen and it forms this kind of dent in the membrane okay holding all that neurotransmitter there dynamine the gtpase comes in and helps to close off that dent and form like a bubble an interior bubble and then pinch and snip it off and so that the membrane closes back up and it's coated at this point in clathrin clathrin c l c l a t h r i n and this forms a new vesicle filled with neurotransmitter so that's clathrin-mediated endocytosis the vesicle then returns to the whole recycling pool where it can later be released other methods of removal of neurotransmitter from the cleft we covered a few we covered transporter removal we covered volume transmission if they float away we covered autoreceptors shutdown of release right a couple of different things here diffusion that's your volume transmission okay the the neurotransmitter could diffuse away from the cleft you know it could float away Along The Lazy River right re-uptake re-uptake is the technical term for when the transporter sucks it back up and then clathrin-mediated endocytosis occurs that's called re-uptake and if you want a little corollary to uh The Real World um for the treatment of depression the drugs that that are used to treat depression are called ssris selective serotonin re-uptake Inhibitors they inhibit serotonin reuptake this means that there is more serotonin left floating around in the synaptic cleft and it means that serotonin has more of a chance to bind with receptors so all the sonaratonin receptors get bound up and then there's still serotonin floating around eventually those serotonin receptors are not going to be bound anymore and and the serotonin that's floating around can rebind them so that's one way that it ssris like Zoloft increase serotonin signaling by uh blocking serotonin reuptake specifically they block the serotonin transporter from re-uptaking uh the serotonin another thing that can occur is enzymatic destruction and enzymatic destruction tends to be most prevalent at the neuromuscular Junction it's not as important at other synapses but it's very important that the neuromuscular Junction because it helps get rid of the of the leftover neurotransmitter in the cleft faster than just transporter reuptake and this is important because muscles right we don't want our muscles firing and clenching up when we don't want them to we want to fire an action potential make it do what it needs to do and then immediately have it stop when we're done right so it's very important that um neurotransmitter neurotransmission synaptic transmission add the neuromuscular Junction terminates effectively and in a in a quick manner so to do this there are certain enzymes present at the neuromuscular Junction which will break down acetylcholine the neurotransmitter there and help to to break it down so that's another way and then finally the last type of uh removal or or way that that synaptic transmission terminates is something called desensitization basically the idea here is that over time receptors become more insensitive to the neurotransmitters that bind them okay so it's almost they can only bind so much in a certain span of time okay and gradually they become less and less sensitive that's called desensitization now this is a normal process in the brain okay it's ongoing right all the time uh and then they recover okay but this is something that gets uh goes awry in drug addiction in drug addiction you have an extreme form of synaptic desensitization because you're you're taking drugs which Elevate signaling above normal levels so for instance cocaine cocaine blocks the dopamine transporter much like selective serotonin reuptake Inhibitors like zolosh block the serotonin transporter cocaine blocks the dopamine transporter so that means there's more and more and more dopamine hanging around than there should be more dopamine binding but it also means that the dopamine synapses are going to desensitize over time because there's way too much dopamine and they're getting bound getting bound getting bound they get tired okay but not only do they get tired and desensitized but another thing happens in drug addiction after a while they actually will get withdrawn into the cell it's called receptor internalization the neuron will say the postsynaptic neuron says hey you know what this is way too much dopamine signaling this is impacting my ability to function normally and so what I'm going to do is if there's going to be all this dopamine hanging around I'm just going to pull back some of my receptors so that the dopamine can't keep binding at the same level that it's been doing receptor internalization this happens big time with cocaine abuse also in methamphetamine abuse big time and this is one of the reasons in methamp by methamphetamine uh has the worst rates of recovery of almost any drug because the receptor internalization and desensitization is so strong with methamphetamine abuse it lasts years before the individual recovers and so what happens is you stop taking the drug say methamphetamine methamphetamine also elevates dopamine signaling among other things you stop taking methamphetamine and now your brain has less receptors for dopamine Etc and so now the normal amount of dopamine that your brain releases is not enough for your brain to Signal dopamine at normal levels you are beneath basal signaling levels and so this causes all sorts of mood disruptions and issues in these individuals that can persist for years let's talk about uh the neuromuscular Junction I I promised we were going to bring this back and I was hinting at it in the last slide when we talked about enzymatic destruction at a synapse and I said that uh enzymatic destruction is really something that is happening primarily at the neuromuscular Junction what are the reasons for that well because we need to terminate synaptic communication at the neuromuscular Junction rapidly so at the neuromuscular Junction there's something called ache acetylcholine esterase okay esterase it's an enzyme which breaks down acetylcholine so acetylcholine gets released at the neuromuscular Junction presynaptic neuron releases it onto a muscle cell muscle cell depolarizes contracts you got some leftover acetylcholine floating around in the synapse you don't want that acetylcholine to bind again because you don't want that muscle to fire again unless you need it to right so acetylcholine esterase is floating around in the synaptic cleft at the neuromuscular Junction it breaks down acetylcholine into two things it breaks it down into acetic acid and choline acetic acid and choline so acetylcholine is broken down into acetic acid and choline and what happens is that the acetic acid doesn't get used okay it floats off right but the choline does get used it gets brought back to the presynaptic neuron so at the presynaptic neuron here we have specialized Transporters that are specialized for choline they are choline Transporters and they also do one more thing that's special They also take in sodium so when they bring in choline they also bring in a little bit of sodium with them and this catalyzes a secondary reaction inside uh the the cell in which choline is combined with acetyl and it combines with something called cholineal transferase to recombine into acetylcholine so let's break this down again acetylcholine is released to the neuromuscular Junction it binds with a postsynaptic acetylcholine receptor and the muscle cell contracts we need to terminate that though and get rid of the leftover acetylcholine acetylcholine esterase breaks down the leftover acetylcholine into choline and acetic acid acetic acid floats away but choline gets sucked back up by the Transporters on the presynaptic cell the choline Transporters and the choline Transporters bring the choline back in and they also bring a little bit of sodium in this Alters the membrane potential and it allows for the re-synthesis of choline with acetyl into via choline acetyl transferase into acetylcholine acetylcholine gets repackaged into vesicles and the whole process can start over again okay so that's uh mechanisms for terminating uh signaling at the synapse now we're going to talk about a different aspect of synaptic transmission and that's synaptic plasticity so what is synaptic plasticity what does that word mean plasticity or what does it suggest to your mind uh plastic right plastic what what are the properties of plastic plastic is malleable it can be bent it can change its shape right synaptic plasticity then is suggesting that synapses can change their shape right and by that we mean they can form new synapses that can increase their strength they can decrease their strength and increase or decrease communication with other neurons that's synaptic plasticity and it's a process that is integral to learning what is learning okay learning at its most basic uh core is the acquisition of new information and it's one of the things that makes the nervous system such a remarkable remarkable piece of biology is that our nervous systems are are capable of constantly acquiring and rewiring based on information uh they're capable of what's called recursive self-improvement meaning that they can go back and re-edit connections change if you learn something new you you thought something was true but then you later learned that it's false you can go back and change that connection right this is something that artificial intelligence has not approached yet right it's one of the things that separates uh artificial intelligence from general intelligence which is what we have um that ability to to acquire new information and remodel the system based on it all on its own and change the past so the process between this though is something which is called synaptic plasticity now how did we begin to learn about how synaptic plasticity works well there was a physiologist by the name of Donald Hebb in the early 20th century and his idea was that when two neurons are in communication with one another um you got a pre-synaptic and a post-synaptic neuron if those neurons get activated at the same time let's take a look at this image here in the in the lower right get my laser pointer out you got a presynaptic neuron and a postsynaptic neuron okay uh in communication right and look here though this neuron is also receiving information from another neuron that's not what's surprising right we know that neurons are receiving information from all over the place but what happens to these two neurons here if both of them get activated at the same time so this one gets activated and by its neurons wherever they may be and this one gets activated Maybe by this neuron here and they get activated at the exact same time what Donald had was theorizing was that when a pre-synaptic and post-synaptic neuron are repeated or are activated repeatedly together um it creates an and it strengthens the connection between them strengthens the connection between them and so we would say neurons that fire together wire together that was the old saying cells that fire together wired together okay and I'm gonna break this down a little bit further here and I know this this image might look a little bit a little bit intimidating but we'll go through it together and keep in mind this is a theoretical mechanism we'll see in the coming slide that physiologically this theory was born out but the theoretical mechanism here is that you had um external events external stimuli okay going on and these external stimuli memories whatever they they form their own little engrams okay and they're made up of neurons which are connected together which symbolize a particular thing okay maybe a certain stimulus I like to use the example of a ferris wheel let's say you've got a ferris wheel circuit okay and it's a group of neurons together that when they fire they signal the existence of your mind to a ferris wheel or the memory of a ferris wheel or you're seeing a ferris wheel and you recognize that's a ferris wheel right and okay that those those uh engrams those circuits for the ferris wheel they are related to other circuits in your mind where do you commonly see a ferris wheel well at a fair right sometimes other places too like in icon Park in Orlando there is a ferris wheel right it's not a fair but it's a something like that right so you might have the circuit for Ferris wheel which is in connection to another circuit which is related to fair or Carnival okay in your head and it tends to be that when you see a ferris wheel on TV or something it probably activates the carnival circuit or the fair circuit as well and you might remember the time that you were at the carnival right so those circuits are kind of interconnected and they have a strong connection together but what about if we bring some new information in here okay how about uh something like I don't know um popcorn you've got a circuit for popcorn you've had popcorn at a movie theater right but you've never had an affair before okay well maybe one of these days you know you're eating popcorn it's got its own circuit it's not associated with the ferris wheel circuit but then one day you do go to the fair and you smell popcorn all over the place it activates the popcorn circuit at the same time as the ferris wheel circuit is being activated at the same time as the carnival circus being activated and these three circuits become tied together and they form a new circuit the fair Fair Ferris wheel popcorn circuit and now in the rest of your daily life you go to the movie theater whatever you smell some popcorn it also activates the ferris wheel Carnival circuit now and so those memories could get brought up or very easily be brought up this is the idea that cells that fire together wire together okay you get Assemblies of of of circuits which are tied to Memories which are tied to external stimuli and they become tied together over time based on whether or not they're activated simultaneously if you activate two different circuits at the same time they will become tied together and they'll and from that point forward if you activate one of them it's likely you're going to activate the other so that's called heavy and synapses the heavy and synapse mechanism of synaptic plasticity and again it was Donald hebb's Theory but as I as I suggested we're going to see that physiologically this ultimately was borne out through a series of experiments beginning in the 1970s that occurred um looking at the hippocampus now the hippocampus is an area of the brain don't worry we're going to have slides I believe in this module which talk about different areas of the brain and what are their functions and the hippocampus is a really important one it's located in the temporal lobes and the function of the hippocampus is generally agreed to be uh storage of memory memories are not stored in the hippocampus but the hippocampus is almost like the librarian you you bring the books in and the librarian says oh hey these are brand new books where where should they go what section of the library should they be stored in for long-term storage that's what the hippocampus does it takes in new information and it packages it up and sends it out to appropriate circuits of related information kind of what we were just talking about in the previous slide okay so the synapses or the hippocampus is really important for memory right well it stands to reason then that uh synaptic plasticity might be pretty important in an area like this if it's involved in something like memory and learning right and indeed it is we're looking on the right here don't worry I don't need you to memorize these areas of the hippocampus yet that's for other courses uh but we're looking at an area of the hippocampus called the dentate gyrus and there's various axonal connections running through here where information gets sent particularly It Gets Sent From the dentate gyrus through ca3 to ca2 to ca1 along these um Shaffer collaterals and a series of experiments were done in which researchers stimulated the shifter collaterals in one area and measured changes in neurons that they were connected to further on down the line and what they found is that when you stimulate neurons together in this area that are connected together uh at a very high rapid rate it facilitates their firing it creates a state which is called long-term potentiation meaning that they strengthen their connection together and from now on whenever one of those neuron fires it makes it much easier for the other neuron to fire too once again this is very similar to what what Donald had was theorizing and so this is kind of like a form of cellular memory and we're going to break this down a little bit further in the next slide so the researchers stimulated the Shafer collaterals in the dentate gyrus and then they measured the potential changes in cells further on down the line that they were connected to okay so long-term potentiation also known as ltp synapses in ltp behave like heavy and synapses what you do is you apply what's called a Titanic stimulus to um two presynaptic Targets which in which you know the postsynaptic endpoints and this causes a whole bunch of action potentials in the presynaptic neuron and a whole bunch of action potentials in the postsynaptic neurons targets and So eventually if you do this rapidly enough what's going to happen is that they're firing pretty much together okay they're firing together in time and so Titanic stimulus is a rapid strong amount of epsps being sent and it leads to a whole bunch of action potentials in a short period of time but with those two neurons firing Action potentials together in a short period of time this leads to a state of long-term potentiation in which if we take a look at the graph at the bottom here take a moment take a look at that graph and then I'm going to explain what's going on here What's Happening Here is that after the Titanic stimulation is applied if you fire or I'm sorry if you apply small stimuli to those neurons again not Titanic just smaller amounts of epsps what will happen is that the firing between them will will occur much more easily and they'll continue to fire afterward for a period of time so we can see the potentiation of the firing the epsps evoke larger depolarizations and they lead to increased rates of firing together for a long period of time and this ltp long-term potentiation can last for a long time for for hours days even longer months this is at its basic form a cellular form of memory now we're going to break down how this occurs at the level of synapses and molecules here momentarily what you can see on the right is an example of a glutamatergic synapse you have a presynaptic neuron here and it's it's let's it's glutamatergic and it wants to release glutamate onto its postsynaptic neuron wants to excite it depolarize it well we've said that there are two types of glutamate receptors that matter there are ampa receptors and there are nmda receptors there's other glutamate receptors too but for our purposes today these are the most important take a moment to pause the lecture and remind and ask yourself if you remember uh which one of these two ampa or nmda is the simple ligand-gated ION channel that just allows sodium in the answer is that the ampa receptor is the simplest ligand-gated ION channel glutamate binds with it and it allows sodium influx and it depolarizes the membrane but what about the nmda receptor the nmda receptor also binds glutamate but here's the trick the nmda receptor while it binds glutamate it doesn't open up right away it's stuck it's stuck closed because it's got an ion of magnesium which is positively charged jammed inside its pore it's stuck inside there and so glutamate combined but it can't do anything with that nmda receptor not for a while why because magnesium is blocking the pore of the receptor in order for magnesium to be removed from the pore of the receptor because magnesium is positively charged think back to module one think back to electrostatic pressure likes repel Opposites attract if the Magnesium is positively charged you need to drive the membrane potential of the postsynaptic neuron into the positive direction to push to push that magnesium away if the postsynaptic neuron's membrane is positively charged it will force the positively charged magnesium away from the membrane it shoots it out of the nmda receptors in the membrane so it's no longer there now the nmda receptor pore is free and when it's free it does something special it lets in more sodium number one but it also lets in calcium also that's in calcium calcium then goes in and interacts and acts as a second messenger it interacts with a number of second messenger signaling molecules number one protein kinase C and protein kinase C interacts with something called kreb kreb then goes down to the nucleus and interacts with the nucleus and tells it to do something what it tells the nucleus of the cell to do is to generate a retrograde signal remember I said that that most neurotransmission is anterograde but sometimes retrograde happens too it tells the postsynaptic neuron to release a retrograde signal and the retrograde signal is generally nitric oxide nitric oxide so the postsynaptic neuron begins to release nitric oxide from itself and the nitric oxide travels backwards and binds with the presynaptic neuron when it binds at the presynaptic neuron nitric oxide causes the presynaptic neuron to release more glutamate it enhances glutamate release so this is one thing that's happening that underlies long-term potentiation you've increased the amount of neurotransmitter glutamate being released when the presynaptic cell on the postsynaptic you say okay well that might make it easier for the postsynaptic cell to depolarize in the future number two calcium interacts with another second messenger called cam kinase II cam kinase II what cam kinase 2 does is it helps to traffic more ampa receptors to the membrane so it tells the cell hey manufacture some more ampa receptors we're going to bring them up to the membrane put them on the surface so that there are more places for glutamate to bind so you now have two two different processes by which you can strengthen the synaptic connection between these two cells and this is called long-term potentiation number one you've increased the amount of glutamate release from the presynaptic cell onto the postsynaptic and number two you've increased the amount of ampa receptors on the postsynaptic cell for which glutamate can bind to you need ampa receptors because ampa receptors allow for sodium influx to drive up the membrane potential and that's how you can ultimately remove the Magnesium block from The nmda receptors and to allow further long-term potentiation to occur you do these things you facilitate communication between the synapse you make it easier for these neurons to fire together okay let's review quickly we'll go through this with a couple of different figures our key players ampa receptors MDA receptors okay here's another figure demonstrating that ampa receptor activates depolarizes the cell the cell's membrane briefly becomes positive it shoves the Magnesium block out of the repels it away out of the nmda nmda then lets some sodium in some calcium in calcium interacts with pkc kreb Cam kinase II you get increased you get a retrograde signal of nitric oxide increases glutamate release from the presynaptic neuron onto the postsynaptic and you get increased ampa receptors being trafficked to the membrane that is ltp this is going through everything that I just said but we're going to add one more piece of information here um nmda receptors in order for them to function and this shouldn't surprise anything I said to you you know you need the membrane to move in the positive direction right because magnesium is positively charged well the actual membrane potential needs to be above 30 neck 30 millivolts as long as it's above neg 30 millivolts you can start to get activation of nmda receptors remember the membrane potential is reflective of the difference between the uh voltage of the or I'm sorry between the charges outside and the charges inside right so if the membrane is moved into the positive direction here let's take a look at the end result of ltp Edison apps here is before we got a normal synapse okay glutamate hey normally glutamate hits the ampa receptor might depolarize the neuron Etc and you might be asking yourself hey wait a minute if ampa receptors depolarize the neuron and that allows nmda receptors to be activated uh how come ltp doesn't just happen all the time well we go back we think about Donald head and we think about our Titanic stimulus experiments ltp doesn't happen all the time because you need a lot of depolarization in a short span of time you need these neurons to be activated consecutively rapidly in a short space of time together you need lots of stimuli lots of stimulates to trigger ltp under normal circumstances ltp isn't going to occur neurons is going to depolarize maybe it fires an action potential but if another action potential doesn't follow in a short span of time you're probably not going to get ltp occurring okay but let's say ltp does occur here's our difference look at image before image after in the after image we see more glutamate being released and we see more ampa receptors for which the glutamate combined making it more and more likely that these neurons will be strengthened together in their in the future so that's ltp long-term depression what I haven't told you yet is that there is an opposite process okay if ltp is how you form uh you strengthen synaptic connections right you strengthen them together so that uh the activation of one synapse or the activation of one neuron ultimately means another neuron is likely going to be activated too right what about if you want to change neurotr synapses in the opposite way what if you want to reduce the strength of their connection together right so you learn something new and it replaces some old information that is less valid okay you want to you want to undo that connection Maybe here there's another process involved and it's called long-term depression long-term depression now the easy part here is that LTD involves the same players it involves glutamate it involves ampa it involves nmda okay however the difference is that an LTD what you have happening is instead of in ltp you have high frequency uh stimulation producing a fast chain of action potentials producing a fast chain of action potentials close together in time in LTD it's the opposite you have these two neurons firing at a low frequency and they're firing out of sync with one another when they're firing at a high frequency it's very likely that their firing rate is going to sync up right you you deliver a Titanic stimulation in Neuron a it's firing super rapidly causing a lot of firing in neuron B and that's ultimately going to sync up until they're almost firing at the same time together right that's how their connection gets strengthened okay that's how eating popcorn while looking at the ferris wheel forms the connection between the ferris wheel popcorn Carnival circuit right LTD though is when you activate these elements separate from one of one another out of sync so Neuron a is firing uh at a low frequency and it doesn't cause neuron B to fire it fires out of sync with neuron B neuron B is firing based on other influences at different points in time it's got other synapses that it's talking to right so it fires from other synapses talking to it but it's not firing at the same time as Neuron a anymore they're firing out of sync when this occurs LTD occurs it follows and it weakens the connection between neuron A and B so it says basically hey you guys aren't talking as much together anymore so I guess this connection is not as important let's uh sever that connection so that we can have better strength stronger connections with other neurons that are more relevant with other more relevant information okay think about this with the process of learning right Okay so here's the key to this ltp requires the activation of protein kinases okay protein kinases so what happens is you get a lot of ampa activation nmda receptors open up calcium comes in lots of calcium comes in because there's lots of ample lots of nmda Activation so lots of calcium comes in when there's a lot of calcium calcium preferentially activates protein kinases which triggers ltp conversely if there's a little bit of calcium only a small bit of calcium when you've got low rates of firing okay A little bit of nmda activation but not all the nmda receptors small rates of nmda receptors open and they only allow a small amount of calcium in well when you only have a little bit of calcium calcium binds with protein phosphatases instead this is another flow specific mechanism it suggests that protein phosphatases are much more abundant inside the cell than the protein kinases are so it only takes a little bit of calcium to trigger the protein phosphatases when you trigger the protein phosphatases what they do is they remove ampa receptors from the cell membrane they remove ampa receptors and so now it's harder for that neuron to depolarize at that synapse because there's less ampa receptors for the glutamate to bind so we say it's probably likely that there's more phosphatases inside the cell than kinases because it only takes a small amount of cut of calcium to activate the phosphatases conversely you need a whole lot of calcium to activate the kinases so when you get lots and lots of stimulation Co in in in coherent in time together you open way more nmda receptors and then you get activation of protein kinases instead that overcomes the phosphatases and you get added added ampa receptors onto the cell membrane and you also get that retrograde signal signal generator of nitric oxide increasing glutamate release from the presynaptic neuron so for the exam be able to break down ltp the various stages how does it occur what are the key players involved and know that ltp involves protein kinases and LTD involves protein phosphatases let's sum everything up this was a good amount of information in this one here we have learned today about several different types of synapses we rounded out our chemical synapse conversation by learning about the neuromuscular Junction which is a special form of chemical synapse that exists where motor neurons synapse onto muscle cells we learned about a new type of synapse called electrical synapses or Gap Junctions which are formed by special proteins called connexons which form a tube between two neurons where ions pass freely between the two and we learned about volume transmission which is the slowest form of neurotransmission and it's kind of accidental in which neurotransmitters float and get taken up to fuse along the central cerebrospinal fluid we talked about the basic categories of neurotransmitters your amino acids such as glutamate and Gaba your amines such as dopamine serotonin and your peptides such as dinorphin and catholin and we talked about how neurotransmitters are removed from the synapses and then finally we went over synaptic plasticity how learning occurs at the level of ltp and LTD and the importance of glutamatergic synapses for regulating this process