Published October 6, 2011
UB researchers have developed the first transgenic mouse model of a rare genetic disorder that could improve understanding of autism and lead to more targeted treatments.
About 75 to 80 percent of people with the disorder, Timothy Syndrome (TS), develop autism.
The TS mouse exhibits the hallmark characteristics of autism: repetitive physical behaviors, altered social behaviors and impaired communication abilities.
The fact that these behaviors so closely parallel those of humans diagnosed with autism surprised and encouraged researchers.
The TS mutation alters a protein, the voltage-gated L-type calcium channel, causing it to affect how much calcium moves into cells and when.
“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 says. “In understanding the specific, we hope to develop a better understanding of autism in general.”
This research will spur the study of autism at the molecular level, a critical area that has not yet been sufficiently investigated.
“As long as autism is diagnosed by a set of behaviors, it will be an ill-defined condition,” explains Rasmusson, whose son is severely affected by autism spectrum disorder.
“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 individuals present with this condition.”
“Once we determine how TS is related to being diagnosed with autism spectrum disorder, we have an opportunity to explore how 20 percent of individuals manage to override the mutation’s effect,” says Glenna C. Bett, PhD, professor and vice chair of the Department of Gynecology-Obstetrics, and professor 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 conditions, 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 showing that the 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 help them understand 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.”
Bett and Rasmusson described this research in a paper titled Mouse model of Timothy syndrome recapitulates triad of autistic traits, published in the Proceedings of the National Academy of Sciences.
Their co-authors are Patrick L. Bader, Mehrdad Faizi, Leo H. Kim, Scott F. Owen, Michael R. Tadross, Ronald W. Alfa, Richard W. Tsien and Mehrdad Shamloo, all of Stanford University.
Sponsors of the study include the Swiss National Science Foundation, the National Institute of Neurological Disorders and Stroke, the Simons Foundation and the Burnett Family and the National Institute for Mental Health National Research Service Award.