Nov 16, 2015 — New research suggests that small changes in brain connectivity early in life may lead to big changes that contribute to autism and intellectual disabilities. The study, which explores how disruption to the gene Kirrel3 affects the developing brain, could help explain why some people with mutations in the gene develop these conditions. Megan Williams, PhD, assistant professor of neurobiology and anatomy at the University of Utah, explains the research and what's next. The work was published in the journal eLife on November 17, 2015.


Interviewer: New insights into how the brain might be set up differently in certain people intellectual disabilities and autism, up next on The Scope.

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

Interviewer: I'm talking with Dr. Megan Williams, assistant professor of neural biology and anatomy at the University of Utah. Dr. Williams, despite the fact that autism and intellectual disabilities are pretty prevalent, not much is known about the biological changes that take place early on that might set these people down that pathway. But you've found some new insights here.

Dr. Williams: Our new study has shown that there's a very specific defect in connections between neurons in the brains of mice that are missing in autism associated gene. And I think what's unique about our study is that autism and intellectual disability, these are disorders in which it's not going to be easy to see connectivity changes because they're going to be very subtle and probably quite small. It's not like people with autism are missing a whole part of their brain.
And so we've looked at very high resolution at two very specific neuron types and identified a very subtle but very important change in connectivity.

Interviewer: Your research focuses on a gene called Kirrel3. Why did you focus on that gene?

Dr. Williams: I become interested in that molecule almost 10 years ago. It was identified in the C. elegans, which is a round worm, as a very important molecule for synapse formation, and then there started to become a lot of human autism and intellectual disability genomic studies that implicated this gene in these disorders.

Interviewer: And just quickly, what is the synapse?

Dr. Williams: A synapse is the special cell junction between two brain cells, and that's really the essential point of communication between the cells. So your brain cells require synaptic connections really to process any kind of information to see, to hear, to think.

Interviewer: Your research was investigating what defects are caused by changes in that gene. So you approached that question by disrupting that gene or knocking out gene in mice. And what did you find there?

Dr. Williams: Kirrel is expressed in two cells and it probably helps these cells stick together, and because synaptic junctions are places where the neurons sort of stick together and send their signals to one another, it signaled that Kirrel may be important for the synapses between these two very specific cell types. So the two types of neurons that express Kirrel normally have a synaptic connection, and when you're missing Kirrel, they have about one-third fewer of these synaptic connections.
Although that seems like a fairly small change, what happens is it greatly impacts the whole network activity. So all neurons are sort of interconnected to other neurons eventually, much like roads are in a city, and when you disrupt about 30% of them, of this one kind, you end up affecting basically the traffic or the flow of information in the whole brain.

Interviewer: Okay, so that part of the brain is not as active?

Dr. Williams: Actually it's interesting because we're very interested in understanding exactly which synapses might be defective in these disorders. These mice are missing some excitatory synapses, so that means these are synapses that activate the network. But the trick is that these are excitatory synapses that form on inhibitory neurons, so we are really talking about missing excitatory synapses or activating synapses onto neurons that quiet the network.

Interviewer: Okay, interesting.

Dr. Williams: And so this is sort of a double negative and what ends up happening is that we end up exciting the network too much in these knockout mice.

Interviewer: How can we think about that is the idea may be that there's more chatter going on in the brain and it's just harder for the brain to control.

Dr. Williams: That's right. Actually in the hippocampus, this brain region we investigated, synaptic transmission is usually very sparse and that sparseness allows you to have . . . it's thought to allow you to have distinct memories, and so what could be happening is that there's much higher chatter or electrical noise in your brain and it may be sort of inhibiting that encoding of unique memories and they may blur together or not be as crisp and this of course affects learning.

Interviewer: You looked at sort of young mice, do we know whether those changes persist through aging?

Dr. Williams: So we looked at young mice first because this is where these disorders become most diagnosed, but we also looked at older mice, so what we would call adult mice. So it seems like the brains older mice missing Kirrel, though their synapses are not normal, the overall network activity seems to be back to normal.

Interviewer: They kind of compensated for that change later on.

Dr. Williams: That's right.

Interviewer: Could it also be that those early changes might be setting off another chain of events that you just haven't been able to find yet?

Dr. Williams: That's right. In the adult, the older mice, the synapses are still not normal and so especially if the system is stressed, we don't know how the brains would respond. Kirrel3 is also expressed outside the hippocampus, so all our work was in this brain region, but it is expressed in other places and we would imagine it is probably affecting synapses in other brain regions.

Interviewer: And you had mentioned that Kirrel3 had been found to be associated or mutations or variations in that gene was associated with people who have intellectual disabilities or autism. How common was that association seen?

Dr. Williams: Autism linked genes are still only a few percentage of people with autism and Kirrel is one of these and it's still going to be very low percentage of people that have autism and intellectual disability. So this is common and this is one of the reasons we know so little about the brain changes underlying these disorders, but as the buzz words of personalized medicine grow and genome sequencing becomes easier, it's possible that in the future patients with autism and intellectual disability if we can identify their mutation that caused it, if it is a genetic cause, then knowing if they have a Kirrel mutation and whether what the exact defects are in the Kirrel, patients can at least inform those patients' treatments.

Interviewer: Is there anything else you'd like to say?

Dr. Williams: I think one of the really big take-home messages of our paper is that a very small and subtle synaptic defect can have a very big impact on circuit or network function, and so this is why it's really key to identify these very seems so small and possibly insignificant, but these defects in your brain which is hyper connected can amplify to cause some major problems.

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