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The role of SHANK3 in autism spectrum disorders

Joseph Buxbaum, Ph.D.
Mount Sinai School of Medicine

Jacqueline Crawley, Ph.D.
National Institute of Mental Health


The relationship between genetics and autism is not always straightforward, but some autism spectrum disorders are known to be caused by defects in a single gene. These simpler cases give researchers the opportunity to create animal models with the genetic defect and use them to test hypotheses about the mechanisms at work in autism.

SHANK3 encodes a protein that is essential for communication between neurons. Disruptions in the SHANK3 gene have been shown to lead to autism. Joseph Buxbaum of the Mount Sinai School of Medicine and his colleagues have created a mouse model with a similar disruption in SHANK3. The researchers plan to use this model to test their hypothesis that interfering with the expression of SHANK3 disrupts the connections between neurons, leading to overall developmental delays that ultimately result in autism.

A team of four laboratories will use this mouse model to study autism from a variety of perspectives. The Buxbaum laboratory is studying the regulation and biochemical properties of SHANK3. Patrick Hof is looking at changes in the morphology and distribution of neurotransmitter receptors in neurons brought on by disrupting SHANK3. Qiang Zhou aims to record electrical currents from the mouse neurons, a measure of their function, and investigate whether neuronal communication is abnormal in the mice. Finally, Jacqueline Crawley at the National Institute of Mental Health plans to evaluate the ability of the mice to learn and to interact socially, behaviors that are analogous to those altered in people with autism. The researchers hope this multi-pronged approach will provide a well-rounded understanding of the role of SHANK3 — and neurotransmitter biology in general — in the development of autism.

So far in their studies of the SHANK3 model mice, the group has observed reduced expression of glutamate receptors and accompanying deficits in synaptic plasticity — the ability of connections between neurons to change in strength, which is thought to underlie processes such as learning and memory. The deficits in plasticity are reflected in both electrophysiological and structural abnormalities. These findings point to the possibility that glutamate receptors represent therapeutic targets in autism.


proposalCENTRAL #94982