Neurobiology Lecture Notes PDF

Where we are going to be heading on Friday is more about the central nervous system, okay? Where we are going today, we are zooming all the way in and talking about the commonalities of all nerve signaling, okay? Then we will get into the details organized mostly by the kind of neurotransmitter. So...

Where we are going to be heading on Friday is more about the central nervous system, okay? Where we are going today, we are zooming all the way in and talking about the commonalities of all nerve signaling, okay? Then we will get into the details organized mostly by the kind of neurotransmitter. So we are just going to be hitting neurotransmitter after neurotransmitter after neurotransmitter, and then talking about the respective pharmacology that relates to that neurotransmitter. You've likely heard of modulating serotonin, right, to treat anxiety and depression, right? We will also be talking about dopamine, acetylcholine, norepinephrine, glutamate, GABA, right? And there's actually a lot more commonalities than differences in the approach. It's just what neurotransmitter is being modulated as to what effect we're going to see therapeutically. And then we will splay out into the peripheral nervous system within the somatic and autonomic divisions. So we are zooming into our nerves. Again, you're going to love this because you're going to see some of these slides, but different bullet points tomorrow. So basic terminology, because we are a step ahead of Dr. Osell's course, is how these and where these nerve signal, right? So we're going to be talking about messages today that are going to be starting here and either myelinated or non-myelinated axons, and then how they are received in the next nerve, okay? And so dendrites are, you know, they actually, I think they look a lot like osteocytes. Some people tend to think osteocytes look like dendrites. But so these dendritic-like projections, how they receive the signals, how they encode, because we will use examples of one signal, right? It is very, very, very rare that your central nervous system is ever receiving one signal. These neurons have to encode multiple signals, I'm just going to make dots here, that are coming in at any given time, some excitatory, some inhibitory, right? And that nerve is responsible for encoding to tell whether it's going to continue signaling or stop the signal, okay? That signal, then, to be able to be projected or continued, is going to basically come to a head of section of the cell body called the axon hillock. This is where we have a disproportional amount of signaling capability in the form of voltage-gated channels. Down here, as we work our way to where dendrites essentially meet, dendrites is what we have seen before. So this, in essence, while we are signaling this example from nerve to nerve, it looks a lot like what we saw last block, which was what? A neuromuscular junction, okay? So some of these concepts we've covered before were just talking about nerve to nerve rather than nerve to muscle the whole time. This is more of an FYI, but I don't want to get lost on you because we're so zoomed in that nerve morphology very much relates to the individual function and location of a nerve. So, for example, a Purkinje cell down here, look at the complex dendrites compared to what you typically think of a textbook neuron, which is here, where you've got just one or a simple cell body with some dendrites and one projecting axon, okay? So while we are not going to get into this classification system, we'll use that. Dr. Ossl will hit you with that. I think it's amazing, though, that we are still discovering, this was a discovery in the last few years, of different nerve morphology, right? You know, we don't know everything about the body yet. And there are still discoveries taking place. This is, if I remember, it's called a rosehip neuron. It looks like a tangle, basically. But there are still more nerve morphologies to be designated. What are those, what? Where are they? Google it for me. I'm pretty sure it's in the brain. But I know it's called, they informally call it rosehip. And I think that refers to, like, the rose of the flower. I don't know much about gardening. I do not have a green thumb. That's why I have the easy plants in my office, not real plants. Inhibitory, GABA. Yep, no, GABA. Oh, I was writing with the wrong thing, sorry. Let's do this. So I'm just going to write this down, because it does, again, we don't need to know it for the exam, but I'm going to make a point here. Inhibitory, GABA. So what that means, does anyone know anything about GABA ahead of this class? Yeah, Gabby. Can you say it a bit louder? Okay, so Gabby's saying something about the action being reversed. You're close, okay? I'm going to fill in with the terminology we're going to use in the context here. GABA is known as an inhibitory neurotransmitter, okay? She was kind of saying reversed. We're not going to really think about reversing more of just inhibitory, okay? It's going to, and this relates to slides that are later in lecture, inhibitory neurotransmitter signaling, okay? An IPSP, okay? IPSPs, we're going to talk about IPSPs and EPSPs. EPSPs being excitatory. All right, so no exam level takeaway here. More of just an appreciation that while we are going to classically talk about it in this matter, their morphology is very diverse based on the role that they play in the body. All right, so let's recall the directionality we have in relaying these signals. We have sensory receptors that are in the peripheral nervous system that are responsible for signaling to the central, that is supposed to be a star, central nervous system, okay, that then will relay back to the peripheral nervous system via a motor efferent neuron and will have the terminal effect, usually muscle or gland, okay? What I mentioned about the basal ganglia circuit involves from here to here is what we are going to primarily cover, okay? And that is enough in terms of what we feel like is an adequate understanding of basal ganglia. Again, we are staying on the level today of more of how do these, how does a general nerve signal? And we've seen this orientation before when we introduced acetylcholinesterase inhibitors, right? We talked about acetylcholine last block in the context here, right, within the somatic where we have acetylcholine that binds a skeletal muscle, specifically the nicotinic receptor. Was nicotinic ionotropic or, and I'm going to use a new word, metapotropic, ionotropic, right? We're going to talk more about metapotropic now that we're talking about nerve signaling at length, okay? And as you'll notice here, within signaling, acetylcholine is used broadly, right? That's where is the neurotransmitter. That is why we see the generalized cholinergic adverse effects, right, of some of the drugs we had discussed prior. So let's go through the action potential basics, some of which are unique to nerves, but you'll notice a lot of parity from what we've already talked about in muscle. So there's what's known as a threshold potential. We've seen that, right? And there's the concept of all or nothing. This all or nothing concept here very much relates to the encoding that happens in nerves, okay? And that unlike muscle, especially skeletal muscle, it's contractor relaxed, contractor relaxed, contractor relaxed, okay? There's less of a spectrum than there is in nerves, where there's sometimes opposing signals arriving at a nerve. And there's a threshold at which needs to be achieved by enough, for example, EPSPs, excitatory stimuli, for subsequent signaling to occur, okay? I think that might be where Gabby was talking about reverse, because sometimes IPSPs can essentially cancel EPSPs. There's the overshoot, which is simply where our action potential crosses over zero millivolts. And we have the after potentials, which we've seen before here, right, and skeletal muscle. It doesn't just come right back to our resting membrane potential. What we see on the left is a bit more information than what we covered in our last block. So we talked about generally that these voltage-gated sodium channels help relay signals, for example, down a T-tubule, okay? What we didn't mention as much, because it relates more to this unit, are the movement of potassium in conjunction with sodium, okay, to ensure that this action potential occurs. So some added information, compared to what we learned last time, is that at a resting membrane potential, which we see here, minus 90 is just your typical resting membrane potential of nerves. Usually nerves are going to have a greater, in terms of negative, they're usually more like minus 90, as opposed to muscle, which can be more like minus 50, minus 70, okay? That when activation occurs via a change in local voltage, you have the activation gate open, okay? It lets sodium in, and then upon repolarization, what's called inactivation gate closes, okay? So we just kept saying open, close, open, close, open, close. But in reality, it's two different gates that are opening and closing, okay? But remember how fast this occurs, right? Because we're talking about, now we're talking about nerve movement, okay? And the conduction of nerves, which when we're especially talking about motor nerves, needs to be done very, very, very quickly. And we'll get to how quickly in just a minute. But then to cause repolarization, we need potassium movement as well. And so you notice this voltage-gated potassium channel, it's just got one gate, okay? And at resting, it's closed, and it is slower activated. And what we mean by slower activated is the millivolt to which it is activated. It opens, and potassium is going to flood out, to aid in that after potential and to achieve resting membrane potential. I would say go back to resting membrane potential. This actual potential propagation can be broken up roughly into four main steps. There's excitation, initiation, propagation, and recovery. And if we zoom back out to a whole neuron here, we were just looking at basically this, okay? So that action potential, and this is sometimes a point of confusion here, there has to be subsequent action potentials all the way down this, okay? This axon, regardless of how thick the axon is, and regardless of myelin status, whether myelin is present or not. I think sometimes we get in the habit of thinking, oh, there is an action potential, so then the neurotransmitters are going to be released, okay? This has to be propagated, which is why that step is called propagation. We have excitation in the dendrites out here. We have initiation, which is signaling at the axon hillock. We have propagation, which is continuing that change in membrane polarization. And then we have recovery, which just means the recovery of the membrane potential along the axon. So let's break down each one of these. So the first one is neuron excitability, and we're going to relate that to diameter and insulation. You will learn a lot more about diameter and different locations of these neurons with Dr. Ocel. We're going to generally classify them in relation to their speed, okay? So the smallest of diameter, which is considered a slow axon, is unmyelinated, okay? And the nerve diameter is very small. You don't need to know the length or the width, but it's small compared to our other groups. And then hallmark to this type of axon, small diameter axons, is visualized here, okay? So there we go. Let's put that there, okay? So if this is axon and we have an action potential that is trying to be propagated, you notice that the spacing of these voltage-gated sodium channels, now, remember, there are also potassium channels here, which is highlighting sodium, okay, is very close together, okay? It's very close together to aid in that relay of membrane depolarization to allow the subsequent voltage gates to open and allow sodium in, okay? This results in pretty slow conduction, okay? It's kind of very much like a relay race, you know? Usually, there are four participants, you know, in a relay. If you suddenly added four compared to 12 and the baton had to be handed off 12 times, my money is on the four-person relay, you know, versus the 12-person relay. This equates in roughly conduction speed of five to two meters per second, okay? So I think it's more helpful to think of this in, like, miles per hour. So this is about two miles per hour, just for your knowledge, just for fun, okay? So a walk, essentially, on a treadmill, right? Maybe a slight jog. Walk to jog is pace, okay? Let's compare that to our larger diameter axons, of which they are just classified as faster and fast, okay? But the hallmark here is larger diameter axons have myelin, okay? And so when you think of myelin, what do you tend to... What comes to mind with what you've already learned about myelin? Insulation. Good. I heard insulation. Anything else? Can you say it a little bit louder? Nodes around VA. Yep. Mm-hmm. Yep. That relates to, you know, insulating. You can almost think of it insulating the action potential, right? Very good. So axon is, in essence, a protective sheath, if you will. It's lipid-filled sheath that wraps around larger diameter axons of larger nerves. But it also allows for further spacing of these voltage-gated sodium channels, okay? So if you want to relate it to our silly relay, this now allows, instead of a four-person relay, it's a two-person, two really fast people relay, okay? And it allows the spread of that change in current to go further, okay? So what we mean... Let me get my pointer back. What I mean by that is if you look at this example here, okay? Because myelin plays an insulation type of role, the change of membrane potential is insulated inside the cytoplasm of that axon, okay? It's less likely to escape. I like to think of it as not fizzling out, right? The change in charge fizzles out less when you have more myelin there. So it allows further spacing of those voltage-gated sodium channels, right? And faster conduction down that axon. So 30 meters per second is about 66-some-odd miles per hour, okay? So good cruising around 465 speed, right? I guess technically I think 465 is like 55, but whatever. Be careful going 65 even on 465. Oh, some people fly around 465. Oh, some people fly around 465. Okay. So where our fast axon, this is a good one to be located in Indianapolis, 100 meters per second is 224 miles an hour. That is as fast as some of the qualifying speeds of Indy cars. So have you ever been to the Indy 500 qualifying? I'm not a race person myself. I don't know much about it, but it's really neat to see at least once. When they come around full speed, it's incredible. But that is as fast as these motor neurons, which we're going to talk about more on Friday, are actually conducted. Pretty impressive when you put it in miles per hour and just how fast that means. Again, also relaying that we're talking about ion channels opening and closing. That quickly, right? And the current having to spread down that motor neuron that fast. Pretty incredible. Do you need to know those miles per hour? No, you don't need to know the speed. The take-homes here are the larger the axon. In addition to myelin, even just the axon being thicker is more insulative than a smaller diameter axon, okay? It has more insulation properties. So let's tie this to a disease you likely have heard of, which is multiple sclerosis, okay? You notice there is a learning objective, and so I want to make it clear what the expectations are here. The expectations are just relating the physiology of myelin to this disease state of multiple sclerosis. So in your prior experience with multiple sclerosis, how would you characterize the clinical effects of multiple sclerosis? How does it manifest itself? Has anybody had any experience with this disease? Which is generally a demyelinating disease of the axons. Yeah, anything? Mm-hmm. Yeah. Tremors. Yep. Pretty extreme. Yep. Mm-hmm. Yes, so it's involuntary tremors, and they can be flare-ups as well. So there can be time periods where people that experience MS exhibit no physical signs of MS. In fact, some of the first nerves that are often implicated in this disease are the optic nerves, and people can experience blurred vision. It can be before some of the tremors. I would really encourage you, especially because we're at the beginning of our block here, to listen to Dot's story on our Canvas page. Dot is a farmer in northeast Ohio, and our student Casey interviewed her. Casey grew up on a farm, working on a farm, and not only does Dot, but Dot's sister also has MS. And while there is no known cause, they think it could be a multi-hit hypothesis and that two things, maybe genetic predisposition and environmental, you'll hear about Dot theorizing about is there something in the water in my hometown, you know, that might be causing this. So again, it's about 15 or 20 minutes. I would encourage you. She also has a really strong message. She is determined to not use a wheelchair. For her, that was her hill. She said on there that I have MS, MS does not have me. And that goes to empowering the patient. You will notice, especially when we try to emphasize in this unit in particular, we're going to refer to these patients as people that experience anxiety, people that experience depression, people that experience MS, you know, not a depressive patient, not anxiety-ridden patients, putting the people first, okay? You can do that with any of the diseases that we talk about. A person with type 1 diabetes, not a type 1 diabetic, right? Powering the people first in these situations. So as highlighted here, the symptoms, you can associate this back with what we would know physiologically about myelin. It's supposed to help conduct messages quickly as well. So the tremors are a dysregulation in that signaling, which we will tie back a little bit more as we get to the motor neuron signaling and why tremors exist, okay? Because tremors can result from two different scenarios. Sometimes it's inappropriate upregulation in signaling, which can result in tremors, but you can also have tremors related to not enough repressive signaling as well, okay? So that's where the presentation of tremors could still mean a lot clinically as to what pathophysiologically is going on underneath the surface there. Okay, and then in relating initiation and propagation, initiation just refers to the crossing of this threshold, and then propagation refers to what we've covered as essentially that current that is important to be able to continue relaying that signal down the axon. And then finally, we have recovery, which is just a reminder. We inserted here, again, this in particular is more of a, you know, this is FYI, this is more of a reminder, right, of all the mechanisms at play, right? So this recovery is not only our slower potassium channels, but it's our sodium potassium ATPase, for example, right? That's always working in the background to try to maintain cellular homeostasis. All right, let's segue now into talking about what I've alluded to as the property of neurons as integrators of multiple signals, right? We introduced this in textbooks as one signal getting propagated and moves on to the next, right? Our bodies are way more complex than that. And what we see here on the right are examples of a weak input versus an intense input. And what you're seeing that we haven't talked about before, these little voltage indicators here, okay? So what we're seeing, okay, so VM is resting memory potential. These are respective occurrences of action potentials, right? So when we talk about what a weak input, that just means there's not a whole lot down here at the axon hillock of action potentials occurring, okay, versus intense stimuli, which is many, many, many, many, many, like a volley of action potentials being received at this axon hillock, which very much relates to the signaling that's received at these nerve terminals, okay? So it's up to the neuron to appropriately say, these are pretty weak, so I'm going to relay a weak signal, versus intense stimuli, it's going to be relayed as intense neuronal signaling. Formally, these are called incoming messages, either excitatory or inhibitory, okay? These are also referred to as EPSPs for excitatory postsynaptic potential and inhibitory postsynaptic potential, or IPSPs, okay? So what happens during an EPSP? Well, excitatory, we want you to think of sodium, a rapid influx of sodium. I took this image from our draw to know it, and it just conveys what we've already known, I just, no, I just want you to associate, it's that voltage-gated sodium channel that drives membrane towards depolarization by, in essence, causing lots of positive ions to be drawn into the cell. So this would more likely result in depolarization, right? So this is going to try to lead to depolarization, okay? So if we're looking at, like, this is zero and the resting membrane potential is minus 90, right? That new resting membrane potential is going to be moving this way, right? Because it's causing a depolarization where inhibitory postsynaptic potential is hyperpolarization, okay? So it would be driven away from zero, let's say minus 120, for example, okay? So associate inhibitory postsynaptic potential with helping manipulate the membrane potential to make it more challenging, in essence, to cause an action potential, right? So we're essentially just playing around with ions as making it either easier to depolarize and cause an action potential or harder in the sense that we're hyperpolarizing, we're moving it away. And so it's harder to then, for example, if a nerve receives a lot of IPSPs, okay, and it temporarily causes that membrane to be at minus 120, okay? That is going to cause it to be very, very, very challenging to have a subsequent depolarization of this new resting membrane potential to cause signaling. That means it would need a lot of EPSPs if we were at minus 120, for example. Sometimes it helps putting numbers to it to think about it in terms of manipulating what's going on during an IPSP versus an EPSP. What we see down here is the ions responsible for inhibitory postsynaptic potential. And this would be potassium efflux, which we have talked about before. But why would it be chloride influx? I'm seeing this. What do we mean by this? Could we put words to that? Yeah, Adrienne. Right. Based on which way it's moving, right? If we have positive ions like potassium leaving, right, efflux is out, exit, right? That's going to dry the resting membrane potential down. But also you can achieve that by causing negatively charged ions, more negatively charged ions in. Just make sure we're all clear there. All right. But we also have to account for this spatial component of integrating these signals. So there's a spatial summation. So new diagram here, if we look at the bottom. All right. We're looking at this resting membrane potential, and it's a subsequent effect when we have multiple signals. These all happen to be EPSPs coming in at the same time. So they summates when they arrive at the same time. It's like one really big signal, but they are on different dendrites. And in this example, all excitatory. The same thing can happen where we have excitatory and inhibitory, right, to where depending on the timing of these on a trace of a membrane potential, the EPSP would look like this and the IPSP would look like that on the bottom, okay, in terms of effect on the resting membrane potential. Put another way, which I think is helpful to look at it on a diagram that overlays action potential like we've talked about here in the middle, is an example of E1 just refers to an excitatory EPSP, and E2 just means there's another one, okay, that's all the numbers are in reference to. And so we see that multiple are going to aid in raising that membrane potential, depolarizing membrane potential to promote an action potential. Where what can happen is we have excitatory and inhibitory, okay. Which is where they could effectively cancel each other out so we don't cross the threshold here. And note that in itself, if we just had one inhibitory, as we mentioned, that resting membrane potential would dip moving away from threshold. And then last but not least, we have multiple signals down the same one, which is temporal, so in time. This is more, I like to think of this as a volley of signaling, okay, down the same axon terminating on the same part of the dendrite, okay. This will also aid, if it's excitatory, in moving that further depolarizing, moving that resting membrane potential closer to zero, okay. So what we have on our diagram here is saying that oftentimes just one little EPSP is not enough to then propagate a signal. It often takes multiple, whether they're temporal or spatial, to cause a convergence, which we see here, multiple EPSPs to result in that action potential. All right, I am going to come back to a summary figure so that we can get through the material. So this figure we have seen before, right. We used it at our neuromuscular junction, okay. The pharmacology of this unit is mostly going to be addressed within the context of this figure, okay. And so it really is just going to be which neurotransmitter we're talking about modulating and how are we modulating it. Are we inhibiting its ability to get back in by a reuptake transporter? Are we inhibiting its degradation by MAOs? Are we changing the ability of the transporter, its affinity to cause reuptake? They all relate back to these main physiological properties of neurotransmission that are seen on this diagram, which so far this is what we know in the context of our course. What I'm going to highlight here is where we have some added information. In this unit we're going to be talking a lot more about these transporters, these reuptake transporters, which is one mechanism to recycle, in essence, let's use serotonin because that's a big one, recycle serotonin back up into the presynaptic nerve. We also have general spillover in that it will spillover into, we don't really have a drug that targets that, but that's another physiological consequence of neuronal signaling is that the neurotransmitter will just wash out of the post-synaptic cleft space. Then we've talked about prior, degradative enzymes like acetylcholinesterase and the class of drugs of acetylcholinesterase inhibitors. We have those kinds of drugs for other neurotransmitters. The how of some of how these drugs work, theoretically, we've covered. It's now associating what neurotransmitter and what disease it is used to treat. Then some of the others that we're going to shine some more light on here in the subsequent slide is the role of calcium. So, so far we've talked about that there are voltage-gated calcium channels only at that nerve terminal. They're not the voltage-gated ion channels that are responsible for relaying that message down the axon. They're suited at that position to allow for when signaling arrives at the nerve terminal to cause calcium to flood into the nerve terminal. It is then going to play an intricate role. It does everything, right? You're like, gosh, just add it to the list, right? It then plays a role in snap-snare signaling. Does that ring a bell for some people? Some? Yes, some? No. Okay. That's right. That's helpful. No. In the timely release of these neurotransmitters from the synaptic vesicles into the synaptic cleft. Okay? So that's another point of intervention that we'll get to with drugs, but we're going to talk about the physiology today. I'm going to highlight a few. We are not going to go through all of these in our class. Okay? Phew. So what we do want you to know is where they fall in these classes. Okay? So we are going to talk more about acetylcholine. It falls into the cholinergic class. Within the monoamines, we'll be talking about serotonin. Within the amino acid, we'll be talking about all three of these, glutamate. We're going to refer to it as GABA and glycine. The amino acid group is the most widely used in terms of abundance within our body. Okay? So disproportionately, if you're going to guess what neuron, it's likely a glutamate, GABA, or glycine in terms of signaling. And then we will also talk about dopamine within the catecholamine. Notice we are – I leave these up here because you've likely heard of the others. But we're going to stay well within that small molecule network. There is not as much widely used drugs that target norepinephrine and epinephrine. You can think of EpiPen as a good example. But generally, not a lot of drugs that are used often are going to target epinephrine due to the manner in which it physiologically is used. Okay? So what I've highlighted here is more of the pharmacology that we will be focusing on in this unit. So let's talk about our synaptic vesicles and neurotransmitter release. Okay? So if we were to orient ourselves, right, where we are, right, we are here, okay, in terms of this membrane here. Okay? Okay? Where we have calcium that's coming in and we need neurotransmitter release into the synaptic cleft in a timely fashion. Now let's remind ourselves this is also happening at like 220 miles an hour. We have things like nerve conduction for motor movement, right? It's absolutely amazing that this moves at this speed. So a couple key players, and I try to color code these based on their roles on the right here. So this calcium influx is known as calcium-dependent secretory event, okay? So we've already talked about calcium-induced calcium release. So this is calcium- dependent secretory event where calcium binds snapotagmen, okay? If this is our synaptic vesicle here and inside it is our neurotransmitters, there are large proteins that can form complexes to promote the catching, like literally they catch these synaptic vesicles. They then tether them to the plasma membrane and then they stretch them so that the synaptic vesicle actually fuses with the plasma membrane to allow the neurotransmitters to diffuse out, okay? So how it does that is that calcium binds snapotagmen here, okay? Snapotagmen, you notice, is anchored into this synaptic vesicle. It then binds, when calcium is present, it's in a conformation to bind this snare complex. The snare complex is made up of these three subunits, okay? And they're, I'm just going to number them here so you can go reference them. A snare complex is made up of three other very large proteins that are capable of facilitating this anchoring and tethering when calcium is present to tether, which we see here. to tether, which we see here. This is the tethering step, okay? And as a continual calcium is present, it will then cause the fusion, okay, which we see in this step over here. So it catches and allows it for tethering with the snare complex and then with an abundance of calcium, it will essentially pull, okay? And that pulling allows for this fusion pore to form and our neurotransmitters to spill out into the synaptic cleft. On the other side, right, whether we're talking about muscle or, well, muscle or subsequent neuronal signaling, there are going to be receptors. So we've covered ionotropic, right? We've been there, done that, right? We've talked about the one on the left, okay? We're adding on metabetropic, okay? So metabetropic are our G protein coupled receptors. These are very, very diverse as well in terms of it's not just in cardiac muscle. It's all throughout the body, but it allows for a diverse response from one. Acetylcholine is the same throughout our body in terms of its chemical structure, but that one neurotransmitter results in a wide range of signaling, whether we're causing muscle contraction in skeletal muscle or a decrease in heart rate. Those are two very different endpoints physiologically that all happen because of the same neurotransmitter. The reason why is because they have very different receptors at the tissue level, okay? Either ionotropic, which means it's ion regulated, or metabetropic, which means we're talking about G protein coupled signaling mediated. So let's highlight the neurotransmitters that we're covering, for those of you that like tables here. And this gives its respective fate, okay? So what happens? So for example, glutamate, it's fate in terms of how it stops signaling, I should say. So this is signal termination, okay? Because we don't want, you know, for instance, a constant heart rate decrease. We need that to stop, right, in terms of regulation. So glutamate, for example, can either be retaken up by glutamate transporters in the neurons or glia. We'll talk about glial cells next time. They're the support cells of our nervous system. GABA is also reuptake, just like glutamate. Acetylcholine, which we've already learned, is degraded by acetylcholines. Acetylcholinesterase, there we go. And then dopamine, norepinephrine, serotonin, these have multiple ways of getting degraded, all of which are pharmacologically targeted. So that's why we're highlighting how are they normally terminated, because we're going to talk about what happens when we pharmacologically target their termination to promote a therapeutic effect. So the ones I've highlighted, I've kept histamine and nitric oxide on there. We are not going to cover them in this unit. And so these, again, are the signals of how we stop these respective neurotransmitters from signaling.