Tony Zador, CSHL

Photo Credit: Tony Zador, CSHL

In the past year, researchers have debuted a growing number of mouse models that they say exhibit the subtle behaviors of autism. In the midst of controversy over whether these mouse models represent autism, one team of scientists is looking for quirks in the animals’ neural circuits.

In October 2007, a high-profile report unveiled mice that carry a mutation in neuroligin-3, which has been associated with autism in people. Since then, about a dozen other models have been proposed, showcasing a grab bag of genetic mutations: some are pivotal players in the development of nerve cell axons, others in synapse formation. One mutation, PTEN, has a strong role in cancer.

As the list of candidate genes for autism grows, experts estimate that at least 30 mouse models of autism will surface within the next couple of years.

“With all of these models, the question now becomes: What do you do once you have the mouse?” asks neurophysiologist Tony Zador of Cold Spring Harbor Laboratory (CSHL).

Although much has been made of the mice’s autism-like behaviors — hovering alone in a corner of their cage or repeatedly sniffing the same spot — no one has yet compared the brain physiology, such as connections between neurons or firing patterns, of these mutant mice to that of normal mice. One study published in June claimed that the neuroligin-3 mouse model of autism behaves no differently than normal mice.

“These autistic mouse models present only more questions,” says Pavel Osten, assistant professor of physiology at Northwestern University. “At the moment, they are the most interesting thing in all of neurobiology.”

Zador, Osten, and CSHL neurobiologist Josh Huang say the common link among the growing number of mouse models of autism is likely to be found not in their social behaviors or communicative abilities, but in the way neurons in different brain regions communicate with one another.

The trio is looking for quantifiable markers of disease, or ‘endophenotypes’, in the brain wiring of two mouse models of autism. “Our goal is to understand the gene mutations that eventually lead to autism or Rett syndrome at the level of brain circuitry: what connections, and what cell types, do they disrupt?” says Huang.

The researchers are also developing techniques to rapidly image an entire mouse brain within a few hours. Standard methods can take about a week, creating a bottleneck between genetic and behavioral research.

“Genetics research has a very high throughput,” says Osten, noting that genome-wide analyses can scan for thousands of genes at a time. Ideally, he says, neurophysiologists would screen various mouse models of these genetic variations at a similar pace. “That may be possible eventually, but at the moment we’d be happy to increase by ten-fold the speed you can look at mouse models,” he says.

Geneticists are optimistic about the approach, even though the team’s first experiments are still months away from publication.

“Right now you have a lot of people like me who are deeply invested in genetic manipulation. But our expertise doesn’t run to the behavioral and systems analysis,” says developmental neurobiologist Gordon Fishell of New York University, who is not involved in the research.

Fishell is working on yet another mouse model of autism by knocking out genes that code for interneurons, cells that dampen electrical signaling in the brain. “Guys like Tony are just such obvious partners for people like me, because they can take [the research] so much further.”

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