Sep 12, 2014

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: Alzheimer's, autism, fragile X syndrome, and memory loss all have something in common. There's a protein in the cell called Arc, which is thought to be an important part in causing all of these syndromes. My guest, Jason Shepherd, an assistant professor in neurobiology and anatomy, is investigating this protein and what it can tell us about how the brain works. Dr. Shepherd, what is it that all of these diseases have in common?

Dr. Shepherd: Well, we think that the way information is stored in the brain is through the way the cells in the brain connect to each other, and those connections are called synapses. A lot of what we're studying is how those synapses work, how they change when you experience something. This protein, Arc, we think is critical for transducing information from the outside, so changing anything you experience or something that you're learning into molecular changes at those synapses in the brain.

Interviewer: So it has to do with memories or learning or both?

Dr. Shepherd: Both. Memories are just learning that's been stored for a certain amount of time. Really, that's the main question my lab is trying to answer: at the cellular molecular level, how is information stored in the brain for the long term? This is really critical for what the brain does.

Interviewer: I can kind of understand how that might work with, say, memory loss and Alzheimer's. But how would that figure in to something like autism?

Dr. Shepherd: The brain evolved to store information and use that information to modulate behavior. The [inaudible 00:01:47] of behaviors that go wrong in autism are very complicated behaviors like social interaction and language acquisition. We think that because this gene is so critical for maintaining those synaptic changes, any way that you can have a deficiency in that gene or it's misregulated, you get cognitive dysfunction.

Interviewer: And an Arc could be a way that the organism, the animal or the person, is processing their environment and learning from their environment.

Dr. Shepherd: Yes. Arc is one of those genes that's really tightly regulated by experience. In a normal brain, if you're just sitting in a room, not learning thing, its expression is very low. As soon as you start to learn something or you experience something novel, the gene gets turned on and the protein itself is highly regulated at the synapse. So it's downstream of all these signaling events in the cell.
The cell really just wants it to be on and off very quickly. A lot of these diseases seem to result from other mutations or something going wrong in one of those signaling events and because Arc is the protein that seems to be doing a lot of the work at the synapse, we think that it's involved in a lot of these diseases because it's sort of the endpoint of those signaling cascades.

Interviewer: What are you investigating?

Dr. Shepherd: Well, right now we're sort of taking a very multi-pronged approach, so everything from trying to figure out what the structure of the protein is, what it's doing at the synapse, all the way to how it affects circuits in the brain. So we have a microscope that allows us to image into a mouse even while it's awake and behaving so we can image the activity of the neurons and how they change during a learning experience.
Then we can see how Arc has changed during that experience. If we manipulate the protein level, what happens to the way the animal learns. We can do that both in a normal mouse as well as in mice that we model those autism spectrum disorders or Alzheimer's or even schizophrenia.
There was a recent study that came out looking at human patients, and one of the exciting things in psychiatric disorders is that we can now sequence genomes of people and find out what are the genetic inheritants, or what are the genes involved in some of these diseases.
One of the sets of genes that have come out are the ones that seem to act at the synapse, and Arc is one of those as well. So we think that there's really tight links between these psychiatric disorders and I think the big issue now is trying to figure out why some are causing schizophrenia, why some are causing bipolar, why some are causing autism. Even within the same family that has similar mutations, you can get all three of those psychiatric disorders.

Interviewer: I mean, we know that these disorders run in families, but yet, sometimes it's not a single disorder. So you think this might be a link?

Dr. Shepherd: Yeah. Because I think the whole question of nature versus nurture is not really a question anymore. It's clearly an interaction of both. So this gene is one of those genes that is in the middle. It's a gene that's regulated by genetics because it's regulated by a bunch of other proteins that are involved in those signaling cascades, but then it's also responsive to the environment so that whatever is happening to the brain and that circuit, that's acting in response to what the organism is doing at any given time.
We know that, obviously, experiences and the environment affect a lot of these psychiatric disorders and when they manifest. So we think that, yes, there could be a link between the two.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.

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