Cortico-striatal synaptic defects and compulsive motor behaviors in mice

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DESCRIPTION (provided by applicant): Animal models are an important tool for studying human disease mechanisms and testing new therapies. We have identified a compulsive grooming disorder in mice following deletion of a key scaffolding component of the post-synaptic density (PSD). The pathogenesis of this behavior in mice may relate to disorders in the Obsessive Compulsive Disorder (OCD)-like spectrum of anxiety disorders in humans. This mouse model now affords us an opportunity to study pathogenesis from gene to synaptic function to circuit to behavior. The experiments proposed will begin to establish these links by delineating how the loss of this PSD component alters post-synaptic composition, synaptic transmission, and cortico-striatal circuitry. We further propose rescue experiments to restore synaptic function at cortico-striatal synapses and eventually to determine the critical circuitry sufficient to restore normal behavior to the animal. In sum, the results of these experiments will advance our understanding of post-synaptic assembly and synaptic transmission at cortico- striatal synapses. These underpinnings are critical to direct future therapies in humans for OCD-like disorders and other entities arising from abnormal basal ganglia synaptic transmission.