Welcome back to my home. I'm out in my yard on a, kind of a muggy gray day. it's been raining so the air feels a little bit like it might start raining on me at any moment now. So, we'll see what happens, but let's keep going. So we're here today to talk about neurotransmitters. So this true facts are second core concept in the field of neuroscience again continuing on in our thinking about the important means by which neurons communicate using electrical and chemical signals. So now we're going to focus on what exactly those chemical signals are. So our learning objectives today are that I want you to be able to name the major small molecule neurotransmitters and neuropeptides in the central nervous system. And briefly state the functions of each and I want you to think with me about the factors that determine the effect of neurotransmitters on postsynaptic neurons. Alright, well let's begin by reviewing what we talked about last time. About the organization of chemical synaptic transmission, and this slide gives you again, an overview of the processes that are involved in chemical synaptic transmission, beginning with the steady state, where we find in the presynaptic terminal a variety of organelles, and of course our presynaptic vesicles that are loaded up with neurotransmitter ready to go. And what happens then with the arrival of an action potential is a wave of depolarization spreads along the preterminal membrane which eventually reaches voltage gated calcium channels. And those channels open calcium rushes in, which is the key triggering event. Which leads to the fusion of the presynaptic terminal membrane and the membrane of the synaptic vesicle. So that happens as the snare complex which is present out here. Twists and tugs and pulls those membranes together once calcium associates with synaptotagmin. And as those membranes begin to fuse they form what we call a fusion pore and that allows for neurotransmitters then to diffuse out of the synaptic. Vesicle into the synaptic left, and from there the neural transmitters can associate with receptors for those neural transmitters in the postsynaptic side of the synapse. And as receptors and transmitters interact typically ion channels open and close. that could lead to the generation of wave depolarizaion in that postsynaptic process. And maybe even with enough summation of inputs that are doing the same thing at the same time, there could be an action potential generated in that postsynaptic cell. Meanwhile, the membrane of the vesicle is recycled back for further activity. And this involves the coating of the vesicle membrane with a protein called clathrin and the association of clathrin with other molecules that facilitate the pinching off of that vesicle membrane and then it's trafficking back into the pool of vesicles that are ready to be filled again with their neurotransmitter and reenter this vesicle cycle. Okay, well let's let that suffice as a brief review of chemical synaptic transmission. Again I would refer you to the animation associated with the textbook animation 5.2 on chemical synaptic transmission. Which will review all of these processes in a nice, short succinct presentation. Alright, well what were here to talk about today is neurotransmitters and neurotransmitters come in two broad kinds of categories based on their structure and these two categories of neurotransmitters interact with different kinds of receptors. So we have two broad classes of neurotransmitters based on the size of the molecules. One category we call, small molecule neurotransmitters for obvious reasons, and then to contrast those small molecule transmitters we have neurotransmitters that are actually small peptides. And so these peptides of course are comprised of amino acids that are covalently bound to one another and sometimes these peptides can be quite sizable. So small molecule transmitters and peptide transmitters. So these two classes of transmitter bind to two classes of receptor. One class of receptor we call ionotropic receptors, these are receptors where the receptor site is actually a part of an ion channel. And that ion channel can open or close when the transmitter binds to the receptor. So these ion channels are called ligand-gated ion channels, with the ligand being the neurotransmitter. The other type of receptor that we'll consider today are called metabotropic receptors and these receptors activate second messenger system. So there are metabolic steps involved and mediating the effect of the neurotransmitter once it binds to it's receptor. Now, our small molecule neurotransmitters can actually interact with both of these classes of receptors. Both the ionotropic receptors and the metabotropic receptors. So right away I want to emphasize to you that if we want to understand the activity of a neurotransmitter, we need to know something about the receptors that it interacts with. And the activities of neurotransmitters, even though the very same cells can be remarkably diverse depending upon what kinds of receptors were expressed on that neuron. Our peptide neurotransmitters, as far as we know, as far as I know, only interact with metabotropic receptors. So as we'll come to see these metabotropic receptors mediate a slower and potentially longer lasting effects in post synaptic neurons. So, we associate our small molecule transmitters primarily, with quick actions and our peptide transmitters generally speaking with more long lasting and slowly evolving actions. Okay, well let's begin with survey of some important small molecule transmitters. Now, for those of your following along in the reading the reading here in chapter 6 goes into more depth than what we'll cover. so I want you to focus on the level of knowledge that I've given you in the tutorial notes and the level of my discussion with you all today. So, let's begin by thinking about these small-molecule transmitters and get a broad functional sense of what these molecules are. So, many of them are amino acids some of the amino acid transmitters that are important in brain and spinal cord function are shown here. They include amino acids such as glutamate potentially aspartate. certainly gamma-aminobutyric acid, or GABA for short, and glycine. So these molecules mediate rapid synaptic effects when they interact with their ionotropic receptors. As I mentioned, they may also interact with metabotropic receptors. So, the small molecule transmitters can also have longer lasting effects, when those particular kinds of receptors are bound. Now, here we're illustrating some of the important small molecule transmitters that you'll want to know about. And perhaps the most important of them all is glutamate. So glutamate is typically considered the major excitatory neurotransmitter in the central nervous system and as you see here it is an amino acid. So short carbon skeleton with the amino group attached to the side, opposite the carboxyl group. So glutamate is involved in various aspects of cellular metabolism but it also is concentrated in synaptic vesicles at the terminals of neurons that use glutamate as a neurotransmitter. Now, this is such an important molecule that we've prepared some animations that talk about the processing of this. molecule as a neurotransmitter, so I would encourage you to pause just a minute and view animation 6.2 on the website that supports our textbook. You can navigate there yourself or click on the hyperlink in your tutorial handout. Well next lets consider acetylcholine. So we are deviating just a little bit from the flow of the handout but that's okay. Acetylcholine is another small molecule transmitter, its not an amino acid but it is a small molecule. And acetylcholine has very important activity both within the central nervous system and outside of the central nervous system. Outside of the CNS, it's the major excitatory neurotransmitter of our somatic motor neurons. So, this is the neurotransmitter that's released on muscle fiber leading to the contraction of muscles. It's also a major excitatory neurotransmitter in autonomic ganglia and it's also the neurotransmitter of many post ganglionic parasympathetic fibers. Within the brain itself, it seems to have an important modulatory role that may be important in various cognitive functions such as attention. Just as an example of how one such small molecule neurotransmitter might be processed, let's take a closer look at a cholinergic synapse, and so we have this illustrated here in figure 6.2. And so, within the presynaptic compartment, we've got the metabolic machinery that's necessary for producing acetylcholine. In this case, acetylcholine is synthesized by an enzyme called choline acetyltransferase from acetyl-CoA, one of the products of oxidative metabolism and choline, a dietary compound that's important for various aspects of nutrition and brain health. Well, acetylcholine is synthesized in the presynaptic terminal packaged into synaptic vesicles, and then released in a calcium dependent fashion. When acetylcholine is in the synaptic cleft it can interact with post synaptic receptors which can be either of the ionotropic or metabotropic variety. And once acetylcholine has been released into the synaptic cleft, it can be degraded by an enzyme called acetylcholinesterase. And when that happens, the choline portion of the molecule is taken back up in to the presynaptic terminal and recycled. To learn more about the function of a typical cholinergic synapse and how all this works, you might want to view animation 6.1 on our website. Now, before moving on to the biogenic amines, let me just back up a moment and talk about the other important amino acid neurotransmitters that we skipped over, namely the two at the bottom here, GABA and glycine. So GABA is short for gama-aminobutyric acid and it's a metabolite of glutamate so glutamate is in the bio synthetic pathway for GABA. Glycine is a different amino acid. Now, both of these amino acids typically have inhibitory activity in the mature nervous system. We'll come back and say quite a bit more about GABA as we go. But for now, let me just highlight that GABA is the single most important transmitter in the brain that mediates synaptic inhibition. Glycine is a very important neurotransmitter. Especially, in the spinal cord where it likewise mediates synaptic inhibition. Glycine also plays an important role at synapses that release glutamate, where glycine serves as a cotransmitter whose binding is important for the activity of one type of receptor for glutamate. Okay, so now we're ready to move on to another class of small molecule neurotransmitter. These are the biogenic amines and these include molecules such as dopamine, norepinephrine, epinephrine seratonin, otherwise known as indoleamine and histamine, based on yet a different carbon ring structure. So these are all amine molecules that are linked to some kind of a ring type of structure and they all have biological activity in the nervous system that tends to modulate the activity of neurocircuits. So unlike molecules like Glutamate and GABA, that mediate rapid synaptic effects. That appear to convey information, as information flows in neural circuits. The biogenic amines, rather, modulate the way those circuits function. And we'll talk more about them, when we see them in context, in structures such as the basal ganglia of the forebrain. but it's worth emphasizing here that these substances are very important in motivation and rewards systems, such as the compound dopamine. Dopamine's also critical for modulating movement in circuits such as the basal ganglia. And it's involved in activation of circuits in the prefrontal cortex. This is very important and helping to mediate various aspects of cognition. Likewise norepinephrine is also very important in cognitive functioning. It seems to be a part of what it means to pay attention is to have a heightened release of norepinephrine, along with other molecules such as acetylcholine. Another important small molecule transmitter among the biogenic means is serotonin. And together with dopamine, seratonin and dopamine together seem to account for many of the diagnostic categories that we encounter in psychiatry and the human behavioral sciences. In fact most of the drugs that are prescribed to treat psychiatric illness act on modulating the activities of dopamine and serotonin synapses in the brain.
