Mouse mirrors severe form of autism

U. BUFFALO (US) — The first transgenic mouse model of a rare and severe type of autism is expected to improve understanding of the disorder and help researchers design more targeted treatments.

The mouse exhibits not only the repetitive physical behaviors, altered social behaviors, and impaired communication abilities associated with Timothy Syndrome (TS), a severe and rare form of autism, but also mirrors behaviors linked to autism spectrum disorder in general, a surprising and encouraging findings, researchers say.

“This animal and the syndrome that it is associated with provides one of the best chances to understand the underlying mechanisms of autism,” because the link between the two is very strong, says Randall Rasmusson, professor of physiology and biophysics at the University at Buffalo.


“Most genetic mutations linked with autism increase the chances of having autism by a very small factor. In contrast, 75 to 80 percent of people with this Timothy Syndrome mutation have autism spectrum disorder.”

The mutation alters a well-known protein, the voltage-gated L-type calcium channel, causing it to affect how much and when calcium moves into cells.

“The fact that TS arises from such a well-defined alteration in a well-known ion channel gives us the opportunity to study the specifics of this one particular route to autism,” Rasmusson continues. “In understanding the specific, we hope to develop a better understanding of autism in general.”

The research, published in Proceedings of the National Academy of Sciences, paves the way toward understanding autism on the molecular level, a critical component not yet sufficiently explored.

“As long as autism is diagnosed by a set of behaviors, it will be an ill-defined condition,” says Rasmusson. “Once we start to determine some definitive biomarkers, possibly, as this research suggests, calcium handling indicators, we will be able to appreciate the differences between how different individuals present with this condition.”

That understanding will have implications for treatments, too, because while 75 to 80 percent of patients with the mutation were diagnosed with autism, 20 percent were not.

“Once we determine how TS is related to being diagnosed with autism spectrum disorder, we have an opportunity to explore how that 20 percent of individuals manage to override the mutation’s effect,” says co-author Glenna C.L. Bett, professor of gynecology-obstetrics and of physiology and biophysics. “Those mechanisms are likely to play a key role in developing interventional therapies for autism spectrum disorder.”

The research also has the potential to help in modeling and understanding other psychiatric disorders, such as bipolar disorder and substance abuse and dependence.

Bett and Rasmusson were originally conducting research on calcium channels and their effects on heart function when they learned of research published in late 2004 showing that this single mutation in the L-type calcium channel could lead to Timothy Syndrome. At that point, they knew that developing a model of TS would be key to understanding the importance of this calcium channel not just in the heart but in other tissues, especially the brain.

“Cellular calcium activity is a dynamic process that can be modulated by behavior, drugs, and the environment,” Bett explains. “By understanding the Timothy Syndrome mutation and the consequences of altered calcium handling, we hope to develop a general understanding of the link between calcium and the molecular basis of brain function. Understanding this link will provide new avenues for pharmacological intervention.”

Researchers from Stanford University contributed to the study that was sponsored in part by the Swiss National Science Foundation, the National Institute of Neurological Disorders and Stroke, and the National Institute for Mental Health.

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