Striatal synaptic Abnormalities in Models of Autism

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DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Recent genetic findings have identified mutations in synaptic cell adhesion genes and genes encoding their interacting protein partners at central synapses as genetic causes of autism spectrum disorders. We have created a novel autism model mouse line based on deletion of neuroligin-1. These mice have selective, excessive repetitive behavioral abnormalities of potential relevance to autism. Our preliminary data strongly implicate a decrease in NMDA receptor function in the striatum as a cause of this repetitive behavior phenotype. We now propose experiments to examine the effect of deletion of this gene on cortico-striatal synaptic function in detail. Furthermore, we propose to selectively rescue/treat this phenotype using genetic and pharmacologic approaches. Thus, we will be able to directly connect a specific synapse in a specific brain region due to a specific molecular abnormality with an abnormal behavior, an important basic goal in neuroscience. These experiments will identify novel synaptic and circuit-level mechanisms for obsessive-compulsive disorder- like repetitive behaviors in general. In addition, we hope to identify novel treatment targets for these behaviors for a subset of autistic patients.