AMPA-receptors and fast synaptic transmission in the brain

Published on January 19, 2015   36 min
0:00
Hello, I'm Stuart Cull-Candy from University College London. And I'm going to be considering some of the cellular and molecular aspects of synaptic AMPA-type glutamate receptor that allow them to mediate false synaptic transmission in the brain. So I'll be considering how the functional properties of these receptors shape the transmission process.
0:22
And I'm going to be covering five main topics indicated in this slide. I'll start by describing broadly, how AMPA-receptors mediate the fast component of excitatory transmission in the brain. Secondly, I'll address the question of how many functionally distinct types of AMPA-receptors are involved in transmission and the functional importance of their topology. Third, I'll consider how AMPA-receptor diversity shapes synaptic transmission and the implications of their differential distribution and plasticity. Fourth, I'll ask how AMPA-receptor structure affects its behavior and properties. And fifth, I'll ask what role do auxiliary AMPA-receptor proteins, such as stargazin, play in controlling AMPA-receptor properties and diversity.
1:12
So let's start by asking, how do AMPA-receptors mediate fast synaptic transmission in the brain? Well, as you know, in the brain, neighboring neurons are in very close proximity, but they're not usually in close enough physical contact for the nerve impulse to jump across the intervening gap between the cells. So to achieve this, a majority of neurons use a chemical transmitter that's released from the presynaptic cell.
1:40
So this next slide then shows a schematic drawing of an excitatory central synapse on the left hand side, with pre and postsynaptic elements together with an EM on the right hand side of a real central synapse, in fact, one that we use for many of our experiments, the mossy fiber to granule cells synapse in the cerebellum, which of course, shows the same elements. And as you know, it turns out that in the mammalian brain, the major fast excitatory transmitter is the simple amino acids glutamate packaged in presynaptic vesicles, a proportion of which release their contents into the synaptic cleft in response to the invading nerve impulse. And glutamate diffusing across the cleft attaches to specific receptor molecules embedded in the postsynaptic cell. These receptors contain an integral ion permeable channel as part of this structure. So when the transmitter binds, the probability of the channels opening increases, allowing positively charged ions to flow into the postsynaptic cell, generating an electrical event. So most neurons, and also quite a few glial cells for that matter, have ionotropic receptors for glutamate, receptors with an ion channel as an integral part of their structure. And these exist in various types. Two of the main ones are indicated here, the NMDA and the AMPA-receptors, which I'll define in a moment. And since I'm going to be focusing mainly on the AMPA-receptors, I wanted to say that functionally speaking, these exist in two functionally distinct forms in the CNS, calcium permeable channels, shown here in blue, and calcium impermeable variety shown in pink. And it's now widely accepted that both are normally associated with auxiliary transmembrane proteins that greatly modify their functional properties and are involved in AMPA-receptor trafficking.
3:38
Well, surprisingly glutamate as a transmitter received relatively little attention for many years. And one of the main reasons for this is because, for a long time, there was general skepticism to the idea that glutamate might be an important neurotransmitter. It's not peculiar to neurons, like many amino acids, it's found throughout the body. And historically, most known neurotransmitters were molecules such as acetylcholine, 5-HT, GABA, and so on, that are mainly localized in nerve terminals, and glutamate didn't seem to fit along with this generally accepted pattern. In addition, central neurons were considered relatively inaccessible to some of the most sophisticated recording techniques, which also tended to hamper progress. As you know, this all began to change with the introduction of patch-clamp recording methods by Bert Sakmann and Erwin Neher. So techniques that were later modified in various ways to provide approaches that could be applied very successfully, not only to cultured neurons, but also to various CNS preparations that have intact synapses formed in vivo and that have all their in vivo properties. And if fact, patch-clamps methods generally work best when applied to small cells such as neuron, since the background noise of the recording is directly proportional to the membrane area. Well, change was also greatly stimulated by the identification of better pharmacological tools by Jeff Watkins and his colleagues, and by advances in molecular biology by a number of labs, notably those of Peter Seeburg and colleagues in Heidelberg, Steve Heinemann and colleagues in the Salk Institute, and Shigatado Nakanishi and colleagues in Kyoto and others. And it's worth bearing in mind that many of the early functional advances made using ionotropic receptors were made in more accessible systems, of course, such as invertebrate tissue.
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AMPA-receptors and fast synaptic transmission in the brain

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