Precise synaptic connectivity is essential for the proper function of the nervous system and defects are implicated in many neurological disorders. However, the mechanisms regulating the assembly and function of synapses in vivo are still poorly understood. As a first step toward understanding the in vivo function of key scaffolding proteins at excitatory synapses we initiated a molecular genetic study on SAP90/PSD95 associated proteins (SAPAPs). SAPAP family proteins (SAPAP1-4) were originally identified as proteins interacting with PSD95 family and Shank family proteins, two other major multidomain scaffolding proteins at excitatory synapses. Together these three groups of proteins have been proposed to form a key scaffolding complex to anchor/target neurotransmitter receptors and signaling molecules to the postsynaptic membrane of excitatory synapses. We found that SAPAP family proteins are widely, yet differentially expressed in the brain. They are highly enriched in the postsynaptic density, and exclusively expressed at excitatory synapses, consistent with their proposed role in postsynaptic scaffolding. In this grant application we propose to combine genetic, biochemical, electrophysiological and behavioral approaches to determine the role of SAPAPS in synaptic development and function, and its implication in obsessive compulsive disorder (OCD)-like behavior. SAPAPS is the only member of the SAPAP gene family that is highly expressed in the striatum, a major brain region involved in pathogenesis of OCD spectrum disorders. We found that genetic deletion of SAPAPS gene in mice results in compulsive grooming behavior leading to facial hair removal and skin lesions, accompanied by significantly increased anxiety. Furthermore, both biochemical and electrophysiological studies reveal cortico-striatal synaptic defects in the mutant mice. These data strongly suggest that SAPAPS plays an important role at cortico-striatal synapses, and thus provide us a unique opportunity to dissect the synaptic mechanisms leading to the development of OCD-like behavior in mice. Obsessive-compulsive disorder is the second most prevalent neuropsychiatric disease, affecting ~2% of the population. This study will use the power of mouse genetics to determine how defects in neuronal connectivity may contribute to the pathogenesis of obsessive-compulsive disorder. ? ?
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