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The many faces of the AMPA-type ionotropic glutamate receptor

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Derek Bowie brings together nine timely reviews from researchers whose work has brought renewed focus on AMPA receptors (AMPARs), the predominant neurotransmitter receptor at central synapses.

Image courtesy of interviewee. June 11, 2024

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This video discusses the role of ionotropic glutamate receptors in the brain, emphasizing their crucial involvement in excitatory signaling, sensory information processing, learning, and memory. These receptors, particularly NMDA and AMPA receptors, are highlighted for their function and significance in various neurological and psychiatric disorders, including neurodevelopmental disorders like autism and schizophrenia, as well as conditions such as depression and addiction.

Over the past three decades, research has shown the need to explore the complexities of these receptors further, which includes understanding their molecular interactions and contributions to brain plasticity and synaptic function. This video mentions key historical figures and findings that have advanced the knowledge of glutamate receptors, including the discovery of their classes and subtypes.

Recent studies suggest a complex functional role of AMPA receptors beyond initial perceptions, especially in relation to their auxiliary proteins, which affect receptor behavior and trafficking. Ongoing research is directed towards identifying genetic mutations linked to AMPA receptors and discovering how these may relate to conditions like autism and intellectual disabilities. This video concludes with a notion of optimism that with the evolving understanding of glutamatergic synapses, more effective therapeutic interventions targeting these conditions could be developed in the near future.

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I guess the way to think about inotropic glutamate

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receptors is that they're really involved in all the,

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excitatory information that comes into the brain.

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So everything, almost everything you can think

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of you could be doing is driven within the brain on a very,

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very short time scale by inotropic glutamate receptors.

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And if I can kind of break that down a little bit.

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Uh, so it brings, it's evolved in bringing all the sensory

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information into the brain.

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So you and I are, having a conversation.

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We can see each other, we can hear each other,

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we can feel the temperature in the room, of course.

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So all of our sensory inputs are all carried into the brain

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by the activity of these very important signaling proteins

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that are found, in synapses.

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But they do much more than that.

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They not only do they bring information into the brain,

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but once that information's brought into the brain,

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then inotropic glutamate receptors at this molecular level

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are involved in, learning

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and memory, mechanisms that in the brain.

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So for example, that sort of internal kind of voice

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that's in your head that's talking about, I have

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to prioritize different kinds of information.

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I have to remember this, for some

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of the students I'm teaching in class,

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you know, they're thinking about the kings.

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Remember, then all

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of those things are driven right down at the molecular

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cellular level at these, neurochemical,

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it's called synapsis.

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So these are junctions between nerve cells

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where they pass on from information,

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and that information is passed from one, neuron,

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one nerve cell to another.

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Uh, and it's activated.

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It activates this pro signaling protein called an

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inotropic glutamate receptor.

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Um, so, in, in terms of the, the glutamate receptor,

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so perhaps not surprising,

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they're involved in sensory information.

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They're involved in learning in memory.

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And so, of course, over the years,

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and I'm talking now about over the last, three decades

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or so for almost 30 years, maybe a little bit more than

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that, because we can talk a little

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bit about the history of them.

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Uh, they've been imp implicated a whole bunch

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of different types of CNS disease.

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So as you can imagine, then they're very,

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there've been something very attractive for people

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who do basic science or someone like me,

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but also the pharmaceutical industry interested in them

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because they've been tied into a number of different types

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of CNS disorders.

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So they're involved in, neurodevelopmental disorders.

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So that may be a, seem a very

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technical term for most people.

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So that includes disorders such as autism,

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intellectual disability, people with schizophrenia.

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It's also falls under neurodevelopmental disorders.

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They're also tied into the, whole process

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of addiction and depression.

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And then in the aging brain,

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they've been tied into disorders such

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as Alzheimer's disease, Parkinson's,

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even Huntington's disease.

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So, so they, they involve every aspect of our life.

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They're involved in the developing brain

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and they're involved in the adult brain.

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Uh, and then I guess the, the thing that's kind of important

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to bring up, because we're gonna have this conversation

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about a particular type of glutamate receptor,

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what we've learned over the last 30 years

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Is that glutamate receptors are kind

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of divided into the inotropic type.

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I've been divided into three main classes in

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this plus one class.

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So there's the NMDA receptors,

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which are the n methyl DESPARATE receptors.

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And that's important because we're gonna talk about someone

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who developed a drug that identified them.

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And the NMD receptors are very important

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because they seem to be very important in neurodevelopment.

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So you have deficits with in NMD receptor function,

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then you end up with intellectual disability

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and often, sometimes very severe childhood epilepsies,

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and including autism.

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And there's also the, the, the protein

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that we're gonna be talking about,

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which is called AMPA receptors.

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And the AMPA receptors are involved in very,

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very rapid signaling in the brain.

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So they're involved in signaling

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that may only take a few milliseconds, so two

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or three milliseconds, which, which is a timescale

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that most people don't really think about

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unless you're doing neurophysiology.

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And the interesting thing about the NMD receptor

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and the amp receptors is that they are kind

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of like little two brothers working together in synapses.

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So they're often co localized in synapses.

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And that's because the NMD receptors ally shut down

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under normal circumstances,

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and it's only the amper receptor gets activated,

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then you can actually activate the NMD receptor.

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So there's this very important relationship

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between these two different types of protein.

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Uh, the other proteins

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that are involved in glutamatergic signaling

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of the canary receptors, they're important as well,

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but they don't have this fundamental role in the hard wiring

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of circuits within the brain.

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But nevertheless, they seem to be able to regulate,

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if you like, the tempo of different types

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of neural circuits.

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They seem to be able to up

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and downregulate various types of, neural circuits,

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and they've been tied into epilepsy.

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And then there's this kind of, class

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of glutamate receptors,

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which isn't really an inotropic, protein.

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That means they, they don't get involved in transporting

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ions into the cell, which is the signal

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by which glutamate receptors,

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inform neurons of what to do.

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It's a class called delta receptors,

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and they seem to have much more of a structural role

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and then a signaling role within the cell.

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Jeff Watkins and, and,

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and Dick Evans, Richard Evans are, are researchers who,

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did a lot of fundamental seminal work,

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work well working at the University of Bristol.

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And to really understand their work, you kind of have

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to understand the timeframe in which they did that work.

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They did that work. The early work was really being done.

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Um, you know, in the sixties, the late fifties.

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And, and if I just take, the audience back a little bit

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to, in the fifties, the forties

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and fifties, then physiology was really trying to work out

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how the different types of nervous

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tissue communicate with each other.

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So a lot of effort was done looking at the nervous system

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that's involved in regulating, for example, the heart rate.

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So this is called the peripheral nervous system.

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The heart rate, that slows it up, speeds it up.

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And also the nervous system

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that regulates digestion and things.

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And that's all part of a nervous system called,

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the autonomic nervous system.

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And what people have found there is that at these

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chemical synapses, so the synapses were one cell signals

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through a chemical to another cell to cell, for example,

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the heart, the cardiac tissue,

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to make it beat faster or beat slower.

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There was found that there was these specific small

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molecules in the case of the heart, to slow it up.

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It was the release of asal choline,

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which would cause a slowing of the heart,

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or if you are being excited.

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So this kind of fear flight kind of thing

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that you often hear about when someone gets startled, then

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that's the release of a, a a, a neurotransmitter called,

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noradrenaline or if you're North America's non Epinephrine.

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Uh, and those two molecules had been kind of identified.

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And so what had happened in the,

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scientific community was that it was a kind of general idea

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that these small molecules which were involved in the

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signaling in nerve cells were somehow unique only

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to nervous tissue.

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And so now, if you fast forward a little bit,

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not fast forward too far,

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but if you now look in the early mid fifties

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or so, there was a Japanese researcher called hii,

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and you've been interested in looking at,

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at cats and epilepsy.

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And he found that when you dropped a little bit

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of glutamine onto the cortex, of a cat,

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cerebral cortex, which is this kind of part

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of the brain here, then you could get this kind

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of epileptic type activity suggesting

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that perhaps glutamate,

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may be important in signaling in the brain.

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That was kind of, a very surprising result

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because people had tied amino acid glutamate,

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which eventually we now believe is

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that the neurotransmitter, in the brain,

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that was surprising for everybody

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because glutamate had really been tied into metabolism.

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You know, it was a kind of key element of metabolism,

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and it seemed to be very paradoxical to

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what people had found before in the autonomic nervous system

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where they'd found these very unique molecules

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that were only found in nervous tissue like

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acetylcholine and no adrenaline.

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But here somebody was saying, well,

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hold on in the brain you've got

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this molecule called glutamate.

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So people noted it,

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but then what happened is there was a group, in,

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in Australia, headed up by, John Curtis, working

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with John Phyllis.

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And this is where one of our, our, our key characters gives.

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In Jeff Watkins, he was an organic chemist, so someone

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who kind of made small molecules.

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And what he started to do was to try

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and look at some of the chemistry of what was causing this.

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So they were starting to try to play around

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with the structure of glutamate

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and to try to understand that at the same time,

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while they were showing this work here at McGill in

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Montreal, one of my colleagues

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who unfortunately passed away a few years, Chris Kovich

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and John Phyllis, who had previously been in Australia,

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also made the same observations,

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but also seen it across different species.

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So there was this idea, this kind of emerging idea

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that glutamate may be a neurotransmitter in the central

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nervous system, right?

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Which was still something not accepted by everybody.

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So, where I think Jeff Watkins came in,

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who was this Australian gentleman,

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and Dick Evans, who was from the uk, it turns out

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that Jeff Watkins then moved to Bristol to get a,

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a research position, and that's what he meant, Dick Evans.

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And what they started to do was

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to make these selective molecules that could distinguish

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between different families of glutamate receptors,

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which I just mentioned before, the NMDA,

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the AMP and the ate.

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So these found these molecules that seem

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to be selectively activating them, one

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of them being this molecule called NMDA.

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We now have this class of glutamate receptor called an NMD

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receptor, which can came directly from Jeff Watkins work.

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And then the other thing that they found was they found

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that the NMD receptors were selectively

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blocked by magnesium.

09:58.125 --> 09:59.765
They didn't really understand what

09:59.765 --> 10:01.405
that meant in a physiological context,

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but they use it as a kind of tool

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to identify when there were stimulating different parts

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of the brain, if that signaling was in,

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was involving NMD receptors

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or something that wasn't an NMD receptor,

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which they called non NMD receptors.

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So out of that, they actually developed this kind

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of three classes of glutamate receptors, the NMD receptor,

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which was blocked by magnesium.

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And then they had these other classes,

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which eventually became the AMPA receptors,

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which we're gonna be chatting about,

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and then also the canine receptors.

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And so what was very fundamental about that work?

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So that happened in about the mid seventies, 75 or so.

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Uh, so what was important about that is

10:41.125 --> 10:43.205
that allowed everybody who was now coming along

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with much more molecular techniques

10:45.445 --> 10:48.085
and much more microscopic techniques to try

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and dissect out in much more detail.

10:51.025 --> 10:53.725
Um, what was the role of these different families

10:53.725 --> 10:56.245
of glutamate receptors within the central nervous system?

10:56.885 --> 10:58.165
I think, the way

10:58.165 --> 11:01.445
to tell AMPA receptors story is there was a whole bunch

11:01.445 --> 11:04.885
of things happened once Jeff Watkins and, and,

11:04.945 --> 11:07.725
and Dick Evans had sort of developed this pharmacology

11:07.795 --> 11:09.765
with some other people who had developed some other kinda

11:09.765 --> 11:10.805
pharmacology as well.

11:11.135 --> 11:13.805
There was some chemistry work done by Coger Lassen and,

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and Copenhagen at Denmark, which turned out

11:16.205 --> 11:17.405
to be quite important as well.

11:17.985 --> 11:20.765
Uh, but at that point, we're now getting into the eighties

11:20.945 --> 11:22.045
and into the nineties.

11:22.065 --> 11:25.325
And that point, there was a number of technical advances

11:25.325 --> 11:26.805
that happened that allowed people

11:27.265 --> 11:29.405
to actually study these in much more detail.

11:29.465 --> 11:32.405
The first thing is we learned how to, it sounds,

11:32.415 --> 11:34.365
surprising, nowadays,

11:34.425 --> 11:36.885
but we learned how to take nerve cells out

11:36.885 --> 11:38.085
of the brain and put them into culture.

11:38.665 --> 11:41.845
And, and by doing that, you could study things in isolation.

11:41.865 --> 11:42.885
So that was a good thing.

11:43.505 --> 11:46.005
The other thing is that, two, two,

11:46.005 --> 11:48.045
German researchers, Burt Sackman

11:48.045 --> 11:51.125
and developed a, a recording technique,

11:51.245 --> 11:52.725
a recording technique, so you could record

11:53.245 --> 11:54.965
electrical activity on neurons,

11:54.965 --> 11:56.885
called patch clamp electrophysiology.

11:57.385 --> 11:59.125
And people were then able to use that

11:59.225 --> 12:02.685
to actually study in very close detail the properties

12:02.685 --> 12:04.165
of different glutamate receptors.

12:04.165 --> 12:07.525
And what was discovered is that when we were looking at,

12:07.525 --> 12:10.365
these amper receptors, it, they realized first,

12:10.465 --> 12:11.485
for the first time,

12:11.955 --> 12:14.685
that they were really working on a really, really,

12:15.085 --> 12:16.565
a few millisecond timescale.

12:16.745 --> 12:19.605
So they were really the first,

12:19.605 --> 12:22.605
when glutamate was released into these synaptic connections

12:22.605 --> 12:25.605
between nerve cells, then they were the first responders,

12:25.605 --> 12:27.925
if you like it, they were the first ones to respond.

12:28.785 --> 12:31.405
And if you remember, I told you the NMD receptors

12:31.945 --> 12:34.085
are conically blocked with this,

12:34.405 --> 12:37.445
molecule called magnesium, resting membrane potential.

12:37.445 --> 12:40.045
So the n the AM receptors were very important

12:40.275 --> 12:43.485
because the move the membrane potential of cells.

12:43.545 --> 12:46.725
So cells have these, electrical gradients across them.

12:47.305 --> 12:50.045
And by doing that, then the magnesium came out

12:50.045 --> 12:51.045
of the NMD receptor.

12:51.545 --> 12:53.565
And then that triggered a whole series

12:53.705 --> 12:55.525
of important events in inside cells

12:55.525 --> 12:59.285
because NMD receptors transported calcium inside the cells,

12:59.575 --> 13:03.125
which then lead to a whole changes into the,

13:03.305 --> 13:05.645
the efficacy of that synaptic connection.

13:05.645 --> 13:08.485
So it made it stronger or can even make it weaker.

13:08.625 --> 13:11.085
So the first, first kind of thing that happened,

13:11.085 --> 13:13.605
so this is now into the early nineties that was going on,

13:13.855 --> 13:16.245
there was a couple of really important things

13:16.245 --> 13:17.685
that all happened in the nineties.

13:17.825 --> 13:19.845
The first thing was there was the realization

13:20.395 --> 13:22.885
that the insertion of AMPA receptors,

13:22.945 --> 13:26.685
or the removal of AMPA receptors from synapses led

13:26.685 --> 13:29.285
to these long-term changes,

13:29.385 --> 13:32.405
to synaptic signaling within the brain called long-term

13:32.405 --> 13:35.005
potentiation and long-term depression.

13:35.145 --> 13:38.685
And, and it's argued even now that that's a cellular basis

13:38.785 --> 13:41.445
of the kind of memory mechanism mechanisms that we all have.

13:41.795 --> 13:45.205
Okay? And at the same time, there was another series

13:45.225 --> 13:48.045
of groups, and this was primarily headed up by,

13:48.265 --> 13:49.285
two main players.

13:49.375 --> 13:50.925
There was also an additional player.

13:51.345 --> 13:53.085
One was a, a researcher called Peter

13:53.085 --> 13:54.525
Seaberg who was in Heidelberg.

13:54.865 --> 13:56.245
And he started to calm

13:56.825 --> 13:58.485
the different kinds of glutamate receptors.

13:58.605 --> 14:00.125
'cause remember at that time we didn't have their

14:00.485 --> 14:01.885
molecular molecular identity.

14:02.415 --> 14:05.445
There was another group at the Salk Institute in California,

14:05.945 --> 14:08.325
and they started to basically compete with each other

14:08.545 --> 14:09.965
to try and look at all of these.

14:10.745 --> 14:12.525
And they identified four different families

14:12.525 --> 14:14.285
of AMPA receptors that come together

14:14.385 --> 14:16.565
and produce different kinds of properties.

14:17.225 --> 14:19.925
Uh, and so things like RNA editing was discovered,

14:19.925 --> 14:21.805
alternate splicing, something perhaps

14:22.195 --> 14:24.525
that may be on the interest, of,

14:24.585 --> 14:26.285
of people maybe listening to this.

14:26.785 --> 14:28.045
Uh, but a whole bunch of really

14:28.045 --> 14:29.765
fundamental discoveries were made.

14:29.785 --> 14:32.645
And the reason that that was really important is

14:32.645 --> 14:35.925
that once we had a discovery of what the molecular identity

14:35.925 --> 14:37.285
of the amp receptors were,

14:37.615 --> 14:41.565
these very fast acting signaling proteins that respond

14:41.565 --> 14:44.245
to glutamate, then if you know the molecular identity,

14:44.475 --> 14:46.245
then you can make a transgenic mouse

14:46.255 --> 14:48.365
where you knock out the different types

14:48.365 --> 14:49.485
of glutamate receptors

14:49.485 --> 14:51.885
so you can work out which one's important

14:51.905 --> 14:52.965
for brain function.

14:53.025 --> 14:56.205
So it was discovered that if you remove ND receptors,

14:56.205 --> 14:57.565
then it was basically lethal,

14:57.845 --> 15:01.005
likewise with some of the receptors, less so

15:01.005 --> 15:02.645
for the keynote receptors, which kind

15:02.645 --> 15:05.165
of ties into their role being more neuromodulatory.

15:05.825 --> 15:08.245
But then the other thing that happened was that

15:08.795 --> 15:11.845
very early on, some of the big pharma companies said, well,

15:11.845 --> 15:14.645
now we have the molecular identity of these, drugs,

15:15.115 --> 15:16.325
then why don't we try

15:16.325 --> 15:18.525
and develop drugs to some of the disorders

15:18.525 --> 15:20.085
that we've been sort of identifying

15:20.085 --> 15:21.525
with these glutamate receptors?

15:21.945 --> 15:23.045
It turns out that wasn't very

15:23.045 --> 15:24.525
successful in that period of time.

15:24.525 --> 15:25.765
And there's a reason for that,

15:25.785 --> 15:27.005
and I'm going to explain

15:27.005 --> 15:28.725
that in a couple of sentences from now.

15:28.785 --> 15:31.285
But early on in the sort of nineties,

15:31.305 --> 15:33.645
got into the two thousands, that's what happened.

15:34.025 --> 15:36.765
And then because we had these cls then people

15:36.785 --> 15:39.045
who are interested in the structural aspects

15:39.045 --> 15:40.245
of glutamate receptors,

15:40.245 --> 15:42.445
and so one very prominent researcher,

15:42.445 --> 15:43.925
and that was someone called Eric Go.

15:44.665 --> 15:48.685
And he actually was able to do, make the first structural,

15:49.185 --> 15:52.205
composition of, of a glutamate receptor, first

15:52.205 --> 15:53.645
of all, identified a part of it.

15:53.905 --> 15:56.165
And then eventually he, with some of his colleagues,

15:56.165 --> 15:57.205
including,

15:57.265 --> 16:00.205
an independent researcher now called Sasha Ky, come up

16:00.205 --> 16:03.525
with a first full lens structure of an amp receptor.

16:03.705 --> 16:06.845
And all of that really happened within the, you know,

16:06.845 --> 16:09.125
beginning of the nineties till the sort

16:09.125 --> 16:10.285
of early two thousands.

16:10.285 --> 16:13.085
So within 10 years, we got their molecular identity,

16:13.305 --> 16:15.685
we tied them into learning and learning mechanisms.

16:16.065 --> 16:17.125
We got their structure.

16:17.665 --> 16:20.645
And then the drug industry had made a kind of an effort

16:20.645 --> 16:23.845
to try and look at them, decided to give up on that.

16:24.125 --> 16:26.485
Actually, the drug discovery, the drug companies sort

16:26.485 --> 16:29.605
of declared that they wouldn't, look at this anymore.

16:30.385 --> 16:33.405
Um, but it turns out they went back.

16:33.555 --> 16:35.445
They've sort of changed their mind about it.

16:35.465 --> 16:36.885
I'm gonna explain that in a little minute.

16:37.345 --> 16:40.525
And, and so there's, there's one other key piece of,

16:40.755 --> 16:44.645
information that happened kind of now later on.

16:44.665 --> 16:46.165
So we've now got structures.

16:46.665 --> 16:49.405
We know that these amper receptors involved in the learning

16:49.415 --> 16:50.605
mechanisms in the brain.

16:51.185 --> 16:52.885
We can make mice that lacks them.

16:52.885 --> 16:55.125
We could even make small changes to amino acids.

16:55.465 --> 16:58.525
But then a, a really important thing that's come along,

16:58.525 --> 17:00.605
and people perhaps didn't appreciate it at the time,

17:00.745 --> 17:03.245
how significant it was, is there was a,

17:03.365 --> 17:05.605
a researcher called David Brett who was in,

17:05.605 --> 17:06.605
California at the time.

17:07.025 --> 17:08.725
And he identified that,

17:09.085 --> 17:11.445
amp receptors needed these proteins,

17:11.445 --> 17:14.365
these auxiliary proteins that actually bound to them

17:14.785 --> 17:17.125
and then helped traffic them into the membrane.

17:17.505 --> 17:19.005
And then once we're in the membrane,

17:19.345 --> 17:22.645
and this is the key thing, is that they actually started

17:22.665 --> 17:26.045
to change the functional behavior of these amper receptors.

17:26.665 --> 17:29.405
So that was sort of in sometime in the two thousands.

17:29.745 --> 17:33.885
And then since then, in a course of a few years or so, him

17:33.985 --> 17:37.205
and a bunch of other people have actually identified a whole

17:37.205 --> 17:41.085
family is like four main families of auxiliary proteins

17:41.315 --> 17:43.685
that now decorate the amp receptors.

17:43.685 --> 17:45.045
The amp receptors are these

17:45.845 --> 17:47.565
arranged in this tetrameric arrangement,

17:47.985 --> 17:50.385
but then they're decorated by different kinds

17:50.385 --> 17:51.505
of auxiliary proteins,

17:51.875 --> 17:54.345
which then shape the properties of these.

17:55.205 --> 17:56.745
And that's very significant

17:56.775 --> 18:00.905
because first of all, it opens up a whole new, level

18:00.925 --> 18:03.105
of biology that needs to get underst that needs

18:03.105 --> 18:05.665
to be understood, but also started to get

18:06.175 --> 18:08.465
drug companies starting to think about, well, hold on.

18:09.005 --> 18:12.785
Uh, maybe we, we, we should kinda re back rethink this

18:12.785 --> 18:14.345
and go back and start to look at

18:14.685 --> 18:16.665
how we can actually look at these receptors

18:16.665 --> 18:17.745
and, and target them.

18:18.125 --> 18:21.625
If you had asked me 10 years ago, would we still be sort

18:21.625 --> 18:25.385
of trying to work out all of this complexity, receptors

18:25.385 --> 18:26.985
or any other glutamine receptor

18:27.655 --> 18:29.105
that I would've prompt you said to you?

18:29.105 --> 18:31.305
No, I think we're kinda getting towards the end of it,

18:32.005 --> 18:35.745
but I think a key discovery was, I guess two things.

18:35.885 --> 18:39.025
One was this discovery of these, the complexity

18:39.025 --> 18:40.025
of amper receptors.

18:40.025 --> 18:43.745
So proteomic work, for example, that's be done by Bert Fler,

18:43.755 --> 18:46.945
who's in Freberg, who we've been collaborating with.

18:47.445 --> 18:50.025
Uh, and then also, a number

18:50.025 --> 18:52.265
of structural biologists have been able to come up with

18:52.825 --> 18:54.545
structures not only of the amp receptor

18:54.575 --> 18:56.945
with all these auxiliary subunits around it.

18:56.965 --> 18:59.465
So some colleagues of mine, Ingle Gregor,

18:59.515 --> 19:02.985
who's in the Cambridge, a collaborator of mine, Tara,

19:03.755 --> 19:07.785
who's in Vanderbilt, and also KY Eric go still part of that.

19:07.805 --> 19:10.305
So there's three or four labs that really sort

19:10.305 --> 19:13.705
of be showing the kind of, molecular anatomy,

19:13.805 --> 19:15.265
if you like, of the amp receptor.

19:15.415 --> 19:17.745
It's now an amp receptor complex now, right?

19:18.645 --> 19:20.025
And then out of that,

19:20.165 --> 19:22.905
and then our lab has really been involved in trying

19:22.905 --> 19:24.905
to understand how all

19:24.905 --> 19:27.905
of these auxiliary proteins regulate these AMPA receptors.

19:28.565 --> 19:32.145
And what's been realized out of it is that this kind

19:32.145 --> 19:34.865
of simple role that we've given AMPA receptors

19:34.865 --> 19:38.065
where they're really there just to kinda get things going so

19:38.065 --> 19:41.785
that the NMDA receptor steps in transports calcium,

19:42.005 --> 19:44.225
and drives all these plasticity mechanisms.

19:44.615 --> 19:47.585
What we're really realizing now is we're probably at start

19:47.585 --> 19:51.385
of a new, way in which to think about AMPA receptors.

19:51.385 --> 19:53.145
They're clearly doing much more than

19:53.145 --> 19:54.585
what has been considered before.

19:55.205 --> 19:57.385
Uh, and that's something that, you know,

19:57.385 --> 19:59.985
I think the next five, 10 years we're gonna start to,

20:00.045 --> 20:01.105
appreciate.

20:01.765 --> 20:04.945
And, and I guess the most poignant thing about all that is

20:04.945 --> 20:07.265
that while we've been doing all of this work,

20:08.045 --> 20:10.185
it turns out now genetics has got involved.

20:10.285 --> 20:12.425
So in the last 10, 10 years

20:12.525 --> 20:15.785
or so, clinicians working with basic scientists,

20:15.785 --> 20:18.425
including myself, I've identified a number

20:18.445 --> 20:22.065
of different types of mutations, often missense mutations.

20:22.065 --> 20:25.745
So these are mutations in the gene, of,

20:25.765 --> 20:27.465
of different types of AMPA receptors

20:27.465 --> 20:30.505
that when you get a often just a single amino acid change,

20:30.975 --> 20:32.785
then that's enough to cause autism

20:32.785 --> 20:34.105
and intellectual disability.

20:34.245 --> 20:36.745
So there's this sort of emerging idea

20:36.855 --> 20:38.545
that not only AMPA receptors,

20:38.925 --> 20:42.945
but all the proteins that are associated with these synapses

20:43.095 --> 20:45.105
that are called glutamatergic synapses,

20:45.105 --> 20:46.945
and a whole bunch of different kind of proteins in there,

20:47.385 --> 20:50.325
in addition to the AMPA receptors, is if you end up

20:50.325 --> 20:52.445
with some kind of defect there, then

20:52.645 --> 20:55.525
although the molecular origin of the defect is different,

20:55.795 --> 20:57.965
then actually leads on to autism

20:58.025 --> 20:59.365
and intellectual disability.

21:00.185 --> 21:01.485
And that's very exciting.

21:01.945 --> 21:03.005
But what it means is

21:03.005 --> 21:06.485
that our current framework in which we understand amper

21:06.605 --> 21:09.285
receptors doesn't really make sense anymore, right?

21:09.285 --> 21:11.325
Because, we are,

21:11.385 --> 21:13.765
the way we understand amper receptors is the kind of,

21:13.765 --> 21:14.845
they get the thing going.

21:15.265 --> 21:19.685
So the NMD receptors drive all the plasticity and the LTP

21:19.685 --> 21:23.085
and the LTD mechanisms, they don't seem to be

21:23.845 --> 21:28.085
involved somehow in, in many of these, defects

21:28.085 --> 21:30.885
that are found in mouse models of intellectual disability

21:31.025 --> 21:32.045
and autism.

21:32.505 --> 21:34.725
And so I think what's gonna happen is that we're gonna have

21:34.725 --> 21:36.365
to kind of look at things.

21:36.445 --> 21:37.605
I don't think we got everything wrong.

21:37.765 --> 21:41.085
I think it's just that we have to kind of reprioritize,

21:41.305 --> 21:44.285
how, AMPA receptors, for example,

21:44.725 --> 21:47.685
involved in sending signals within neural circuits.

21:48.025 --> 21:51.525
And then how do neuro circuits actually encode things such

21:51.525 --> 21:53.605
as memory, such as memory

21:53.865 --> 21:56.765
and how do they go about, so

21:56.765 --> 21:58.085
that you can actually learn something.

21:58.265 --> 21:59.885
The idea that was all kind

21:59.885 --> 22:02.085
of focused on this one synaptic idea,

22:02.105 --> 22:04.245
but it looks like it's really gonna be an ensemble

22:04.505 --> 22:06.205
of different circuits coming together.

22:06.585 --> 22:07.925
And that's how we learn things

22:07.985 --> 22:09.445
and that's how we remember things.

22:10.915 --> 22:13.695
And then maybe just to finalize on that, to finish on

22:13.695 --> 22:15.095
that a little bit,

22:15.445 --> 22:19.575
because of, the sort of actually hard work with a lot

22:19.575 --> 22:20.695
of family foundations

22:20.725 --> 22:24.095
that have been linked into these genetic mutations,

22:24.095 --> 22:25.495
tied into AMPA receptors

22:25.495 --> 22:27.015
and non types of glutamate receptors,

22:27.605 --> 22:28.935
then they have been very vocal

22:29.035 --> 22:31.255
and they've been very imaginative in raising money

22:31.315 --> 22:33.655
and awareness, getting researchers involved,

22:34.035 --> 22:36.535
but they've now actually started to recruit in some

22:36.535 --> 22:37.935
of the big pharma companies.

22:38.195 --> 22:42.135
So I think there was a kind of hiatus, if you like, in terms

22:42.135 --> 22:44.695
of drug discovery and the need to try

22:44.695 --> 22:47.015
and focus on looking at glutamate receptors.

22:47.035 --> 22:49.175
But now that we have a much more kind

22:49.175 --> 22:51.455
of mature understanding of the complexity

22:51.455 --> 22:53.335
of glutamatergic synapses

22:53.335 --> 22:54.695
and all the proteins that are there

22:54.995 --> 22:58.135
and the kind of things we do, then I think it's right,

22:58.165 --> 23:00.135
it's the moment, right, you know, maybe in the next five,

23:00.195 --> 23:03.455
10 years that it might be possible to actually start

23:03.515 --> 23:06.495
to come up with much more validated targets

23:06.795 --> 23:09.975
and sort of a better approach, to try

23:09.975 --> 23:11.935
and, target autism

23:12.035 --> 23:13.175
and intellectual disability,

23:13.185 --> 23:16.175
maybe these other conditions such as schizophrenia

23:16.175 --> 23:17.775
and depression and even addiction.

** The Critical Role of Inotropic Glutamate Receptors in Brain Function and CNS Disorders

00:00:00 - I guess the way to think about inotropic glutamate receptors is that they're really involved in all the, excitatory information that comes into the brain. So everything, almost everything you can think of you could be doing is driven within the brain on a very, very short time scale by inotropic glutamate receptors. And if I can kind of break that down a little bit. so it brings, it's evolved in bringing all the sensory information into the brain. So you and I are, having a conversation. We can see each other, we can hear each other, we can feel the temperature in the room, of course. So all of our sensory inputs are all carried into the brain by the activity of these very important signaling proteins
00:00:43 - But they do much more than that. They not only do they bring information into the brain, but once that information's brought into the brain, then inotropic glutamate receptors at this molecular level are involved in, learning and memory, mechanisms that in the brain. So for example, that sort of internal kind of voice that's in your head that's talking about, I have to prioritize different kinds of information. I have to remember this, for some of the students I'm teaching in class, you know, they're thinking about the kings. Remember, then all of those things are driven right down at the molecular cellular level at these, neurochemical, it's called synapsis. So these are junctions between nerve cells
00:01:24 - and that information is passed from one, neuron, one nerve cell to another. and it's activated. It activates this pro signaling protein called an inotropic glutamate receptor. so, in, in terms of the, the glutamate receptor, so perhaps not surprising, they're involved in sensory information. They're involved in learning in memory. And so, of course, over the years, and I'm talking now about over the last, three decades or so for almost 30 years, maybe a little bit more than that, because we can talk a little bit about the history of them. they've been imp implicated a whole bunch of different types of CNS disease. So as you can imagine, then they're very, there've been something very attractive for people
00:02:06 - but also the pharmaceutical industry interested in them because they've been tied into a number of different types of CNS disorders. So they're involved in, neurodevelopmental disorders. So that may be a, seem a very technical term for most people. So that includes disorders such as autism, intellectual disability, people with schizophrenia. It's also falls under neurodevelopmental disorders. They're also tied into the, whole process of addiction and depression. And then in the aging brain, they've been tied into disorders such as Alzheimer's disease, Parkinson's, even Huntington's disease. So, so they, they involve every aspect of our life. They're involved in the developing brain
00:02:49 - and then I guess the, the thing that's kind of important to bring up, because we're gonna have this conversation about a particular type of glutamate receptor, what we've learned over the last 30 years Is that glutamate receptors are kind of divided into the inotropic type. I've been divided into three main classes in this plus one class. So there's the NMDA receptors, which are the n methyl DESPARATE receptors. And that's important because we're gonna talk about someone who developed a drug that identified them. And the NMD receptors are very important because they seem to be very important in neurodevelopment. So you have deficits with in NMD receptor function,
00:03:30 - and often, sometimes very severe childhood epilepsies, and including autism. And there's also the, the, the protein that we're gonna be talking about, which is called AMPA receptors. And the AMPA receptors are involved in very, very rapid signaling in the brain. So they're involved in signaling that may only take a few milliseconds, so two or three milliseconds, which, which is a timescale that most people don't really think about unless you're doing neurophysiology. And the interesting thing about the NMD receptor and the amp receptors is that they are kind of like little two brothers working together in synapses. So they're often co localized in synapses.

"The Intricate Role of Glutamate Receptors in Neural Communication and Function"**

00:04:13 - under normal circumstances, and it's only the amper receptor gets activated, then you can actually activate the NMD receptor. So there's this very important relationship between these two different types of protein. the other proteins that are involved in glutamatergic signaling of the canary receptors, they're important as well, but they don't have this fundamental role in the hard wiring of circuits within the brain. But nevertheless, they seem to be able to regulate, if you like, the tempo of different types of neural circuits. They seem to be able to up and downregulate various types of, neural circuits, and they've been tied into epilepsy.
00:04:54 - of glutamate receptors, which isn't really an inotropic, protein. That means they, they don't get involved in transporting ions into the cell, which is the signal by which glutamate receptors, inform neurons of what to do. It's a class called delta receptors, and they seem to have much more of a structural role and then a signaling role within the cell. Jeff Watkins and, and, and Dick Evans, Richard Evans are, are researchers who, did a lot of fundamental seminal work, work well working at the University of Bristol. And to really understand their work, you kind of have to understand the timeframe in which they did that work.
00:05:35 - you know, in the sixties, the late fifties. And, and if I just take, the audience back a little bit to, in the fifties, the forties and fifties, then physiology was really trying to work out how the different types of nervous tissue communicate with each other. So a lot of effort was done looking at the nervous system that's involved in regulating, for example, the heart rate. So this is called the peripheral nervous system. The heart rate, that slows it up, speeds it up. And also the nervous system that regulates digestion and things. And that's all part of a nervous system called, the autonomic nervous system. And what people have found there is that at these
00:06:19 - through a chemical to another cell to cell, for example, the heart, the cardiac tissue, to make it beat faster or beat slower. There was found that there was these specific small molecules in the case of the heart, to slow it up. It was the release of asal choline, which would cause a slowing of the heart, or if you are being excited. So this kind of fear flight kind of thing that you often hear about when someone gets startled, then that's the release of a, a a, a neurotransmitter called, noradrenaline or if you're North America's non Epinephrine. and those two molecules had been kind of identified. And so what had happened in the,
00:06:59 - that these small molecules which were involved in the signaling in nerve cells were somehow unique only to nervous tissue. And so now, if you fast forward a little bit, not fast forward too far, but if you now look in the early mid fifties or so, there was a Japanese researcher called hii, and you've been interested in looking at, at cats and epilepsy. And he found that when you dropped a little bit of glutamine onto the cortex, of a cat, cerebral cortex, which is this kind of part of the brain here, then you could get this kind of epileptic type activity suggesting that perhaps glutamate,
00:07:40 - That was kind of, a very surprising result because people had tied amino acid glutamate, which eventually we now believe is that the neurotransmitter, in the brain, that was surprising for everybody because glutamate had really been tied into metabolism. You know, it was a kind of key element of metabolism, and it seemed to be very paradoxical to what people had found before in the autonomic nervous system where they'd found these very unique molecules that were only found in nervous tissue like acetylcholine and no adrenaline. But here somebody was saying, well, hold on in the brain you've got this molecule called glutamate. So people noted it, but then what happened is there was a group, in,

"The Pioneering Work of Jeff Watkins and the Discovery of Glutamate Receptors"

00:08:23 - with John Phyllis. And this is where one of our, our, our key characters gives. In Jeff Watkins, he was an organic chemist, so someone who kind of made small molecules. And what he started to do was to try and look at some of the chemistry of what was causing this. So they were starting to try to play around with the structure of glutamate and to try to understand that at the same time, while they were showing this work here at McGill in Montreal, one of my colleagues who unfortunately passed away a few years, Chris Kovich and John Phyllis, who had previously been in Australia, also made the same observations, but also seen it across different species.
00:09:03 - that glutamate may be a neurotransmitter in the central nervous system, right? Which was still something not accepted by everybody. So, where I think Jeff Watkins came in, who was this Australian gentleman, and Dick Evans, who was from the uk, it turns out that Jeff Watkins then moved to Bristol to get a, a research position, and that's what he meant, Dick Evans. And what they started to do was to make these selective molecules that could distinguish between different families of glutamate receptors, which I just mentioned before, the NMDA, the AMP and the ate. So these found these molecules that seem to be selectively activating them, one of them being this molecule called NMDA.
00:09:47 - receptor, which can came directly from Jeff Watkins work. And then the other thing that they found was they found that the NMD receptors were selectively blocked by magnesium. They didn't really understand what that meant in a physiological context, but they use it as a kind of tool to identify when there were stimulating different parts of the brain, if that signaling was in, was involving NMD receptors or something that wasn't an NMD receptor, which they called non NMD receptors. So out of that, they actually developed this kind of three classes of glutamate receptors, the NMD receptor, which was blocked by magnesium.
00:10:26 - which eventually became the AMPA receptors, which we're gonna be chatting about, and then also the canine receptors. And so what was very fundamental about that work? So that happened in about the mid seventies, 75 or so. so what was important about that is that allowed everybody who was now coming along with much more molecular techniques and much more microscopic techniques to try and dissect out in much more detail. what was the role of these different families of glutamate receptors within the central nervous system? I think, the way to tell AMPA receptors story is there was a whole bunch of things happened once Jeff Watkins and, and,
00:11:07 - with some other people who had developed some other kinda pharmacology as well. There was some chemistry work done by Coger Lassen and, and Copenhagen at Denmark, which turned out to be quite important as well. but at that point, we're now getting into the eighties and into the nineties. And that point, there was a number of technical advances that happened that allowed people to actually study these in much more detail. The first thing is we learned how to, it sounds, surprising, nowadays, but we learned how to take nerve cells out of the brain and put them into culture. And, and by doing that, you could study things in isolation. So that was a good thing. The other thing is that, two, two,
00:11:48 - and developed a, a recording technique, a recording technique, so you could record electrical activity on neurons, called patch clamp electrophysiology. And people were then able to use that to actually study in very close detail the properties of different glutamate receptors. And what was discovered is that when we were looking at, these amper receptors, it, they realized first, for the first time, that they were really working on a really, really, a few millisecond timescale. So they were really the first, when glutamate was released into these synaptic connections between nerve cells, then they were the first responders, if you like it, they were the first ones to respond.

"The Evolution of AMPA Receptors: Understanding Their Role in Synaptic Plasticity and Drug Development"

00:12:31 - are conically blocked with this, molecule called magnesium, resting membrane potential. So the n the AM receptors were very important because the move the membrane potential of cells. So cells have these, electrical gradients across them. And by doing that, then the magnesium came out of the NMD receptor. And then that triggered a whole series of important events in inside cells because NMD receptors transported calcium inside the cells, which then lead to a whole changes into the, the efficacy of that synaptic connection. So it made it stronger or can even make it weaker. So the first, first kind of thing that happened,
00:13:13 - there was a couple of really important things that all happened in the nineties. The first thing was there was the realization that the insertion of AMPA receptors, or the removal of AMPA receptors from synapses led to these long-term changes, to synaptic signaling within the brain called long-term potentiation and long-term depression. And, and it's argued even now that that's a cellular basis of the kind of memory mechanism mechanisms that we all have. Okay? And at the same time, there was another series of groups, and this was primarily headed up by, two main players. There was also an additional player.
00:13:53 - Seaberg who was in Heidelberg. And he started to calm the different kinds of glutamate receptors. 'cause remember at that time we didn't have their molecular molecular identity. There was another group at the Salk Institute in California, and they started to basically compete with each other to try and look at all of these. And they identified four different families of AMPA receptors that come together and produce different kinds of properties. and so things like RNA editing was discovered, alternate splicing, something perhaps that may be on the interest, of, of people maybe listening to this. but a whole bunch of really fundamental discoveries were made. And the reason that that was really important is
00:14:35 - of the amp receptors were, these very fast acting signaling proteins that respond to glutamate, then if you know the molecular identity, then you can make a transgenic mouse where you knock out the different types of glutamate receptors so you can work out which one's important for brain function. So it was discovered that if you remove ND receptors, then it was basically lethal, likewise with some of the receptors, less so for the keynote receptors, which kind of ties into their role being more neuromodulatory. But then the other thing that happened was that very early on, some of the big pharma companies said, well, now we have the molecular identity of these, drugs,
00:15:16 - and develop drugs to some of the disorders that we've been sort of identifying with these glutamate receptors? It turns out that wasn't very successful in that period of time. And there's a reason for that, and I'm going to explain that in a couple of sentences from now. But early on in the sort of nineties, got into the two thousands, that's what happened. And then because we had these cls then people who are interested in the structural aspects of glutamate receptors, and so one very prominent researcher, and that was someone called Eric Go. And he actually was able to do, make the first structural, composition of, of a glutamate receptor, first of all, identified a part of it. And then eventually he, with some of his colleagues,
00:15:57 - an independent researcher now called Sasha Ky, come up with a first full lens structure of an amp receptor. And all of that really happened within the, you know, beginning of the nineties till the sort of early two thousands. So within 10 years, we got their molecular identity, we tied them into learning and learning mechanisms. We got their structure. And then the drug industry had made a kind of an effort to try and look at them, decided to give up on that. Actually, the drug discovery, the drug companies sort of declared that they wouldn't, look at this anymore. but it turns out they went back. They've sort of changed their mind about it. I'm gonna explain that in a little minute.

"The Evolving Understanding of AMPA Receptors: From Auxiliary Proteins to Genetic Implications in Learning and Neurodevelopment"

00:16:40 - information that happened kind of now later on. So we've now got structures. We know that these amper receptors involved in the learning mechanisms in the brain. We can make mice that lacks them. We could even make small changes to amino acids. But then a, a really important thing that's come along, and people perhaps didn't appreciate it at the time, how significant it was, is there was a, a researcher called David Brett who was in, California at the time. And he identified that, amp receptors needed these proteins, these auxiliary proteins that actually bound to them and then helped traffic them into the membrane.
00:17:19 - and this is the key thing, is that they actually started to change the functional behavior of these amper receptors. So that was sort of in sometime in the two thousands. And then since then, in a course of a few years or so, him and a bunch of other people have actually identified a whole family is like four main families of auxiliary proteins that now decorate the amp receptors. The amp receptors are these arranged in this tetrameric arrangement, but then they're decorated by different kinds of auxiliary proteins, which then shape the properties of these. And that's very significant because first of all, it opens up a whole new, level
00:18:03 - to be understood, but also started to get drug companies starting to think about, well, hold on. maybe we, we, we should kinda re back rethink this and go back and start to look at how we can actually look at these receptors and, and target them. If you had asked me 10 years ago, would we still be sort of trying to work out all of this complexity, receptors or any other glutamine receptor that I would've prompt you said to you? No, I think we're kinda getting towards the end of it, but I think a key discovery was, I guess two things. One was this discovery of these, the complexity of amper receptors. So proteomic work, for example, that's be done by Bert Fler,
00:18:47 - and then also, a number of structural biologists have been able to come up with structures not only of the amp receptor with all these auxiliary subunits around it. So some colleagues of mine, Ingle Gregor, who's in the Cambridge, a collaborator of mine, Tara, who's in Vanderbilt, and also KY Eric go still part of that. So there's three or four labs that really sort of be showing the kind of, molecular anatomy, if you like, of the amp receptor. It's now an amp receptor complex now, right? And then out of that, and then our lab has really been involved in trying to understand how all
00:19:28 - And what's been realized out of it is that this kind of simple role that we've given AMPA receptors where they're really there just to kinda get things going so that the NMDA receptor steps in transports calcium, and drives all these plasticity mechanisms. What we're really realizing now is we're probably at start of a new, way in which to think about AMPA receptors. They're clearly doing much more than what has been considered before. and that's something that, you know, I think the next five, 10 years we're gonna start to, appreciate. And, and I guess the most poignant thing about all that is
00:20:08 - it turns out now genetics has got involved. So in the last 10, 10 years or so, clinicians working with basic scientists, including myself, I've identified a number of different types of mutations, often missense mutations. So these are mutations in the gene, of, of different types of AMPA receptors that when you get a often just a single amino acid change, then that's enough to cause autism and intellectual disability. So there's this sort of emerging idea that not only AMPA receptors, but all the proteins that are associated with these synapses that are called glutamatergic synapses,

"Rethinking AMPA Receptors: Implications for Autism, Intellectual Disability, and Future Therapeutic Targets"

00:20:47 - in addition to the AMPA receptors, is if you end up with some kind of defect there, then although the molecular origin of the defect is different, then actually leads on to autism and intellectual disability. And that's very exciting. But what it means is that our current framework in which we understand amper receptors doesn't really make sense anymore, right? Because, we are, the way we understand amper receptors is the kind of, they get the thing going. So the NMD receptors drive all the plasticity and the LTP and the LTD mechanisms, they don't seem to be involved somehow in, in many of these, defects
00:21:31 - and autism. And so I think what's gonna happen is that we're gonna have to kind of look at things. I don't think we got everything wrong. I think it's just that we have to kind of reprioritize, how, AMPA receptors, for example, involved in sending signals within neural circuits. And then how do neuro circuits actually encode things such as memory, such as memory and how do they go about, so that you can actually learn something. The idea that was all kind of focused on this one synaptic idea, but it looks like it's really gonna be an ensemble of different circuits coming together. And that's how we learn things and that's how we remember things.
00:22:13 - that a little bit, because of, the sort of actually hard work with a lot of family foundations that have been linked into these genetic mutations, tied into AMPA receptors and non types of glutamate receptors, then they have been very vocal and they've been very imaginative in raising money and awareness, getting researchers involved, but they've now actually started to recruit in some of the big pharma companies. So I think there was a kind of hiatus, if you like, in terms of drug discovery and the need to try and focus on looking at glutamate receptors. But now that we have a much more kind of mature understanding of the complexity
00:23:16 - and all the proteins that are there and the kind of things we do, then I think it's right, it's the moment, right, you know, maybe in the next five, 10 years that it might be possible to actually start to come up with much more validated targets and sort of a better approach, to try and, target autism and intellectual disability, maybe these other conditions such as schizophrenia and depression and even addiction.

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