Role of Draxin in Forebrain Connectivity and Complex Behaviors

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DESCRIPTION (provided by applicant): The corpus callosum (CC) is the main fiber tract connecting the cerebral hemispheres and serves to coordinate the transfer of information between them. Malformations in this structure have been observed in neurodevelopmental and neuropsychiatric disorders including autism, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder and Tourette syndrome more frequently than in the general population. As all of these disorders are diagnosed primarily by behavioral criteria, it is importat to know if the CC plays a role in behaviors relevant to these criteria. Commissure development and function studies require tractable animal models. We have identified a mutation in the coding region of the chemorepulsive axon guidance gene Draxin that appears to be responsible for the commissural phenotype seen in BTBR T+ Itpr3tf/J (BTBR) mice. As BTBR also displays several behavioral deficits relevant to the key characteristics of autism, it affords an excellent opportunity to evaluate the role of Draxin mutation in CC formation and autism-relevant behaviors. Our long-term goal is to elucidate the genetic basis of deficits in forebrain connectivity and the impact of these deficits on neurodevelopmental and neuropsychiatric related behaviors. The goal of this R21 project is to determine the role of Draxin in CC development and autism relevant behaviors. The objectives of this research project are: 1) to elucidate the role of Draxin in commissural development in different genetic backgrounds and 2) to determine the importance of Draxin-dependent commissure malformation in behavioral performance. We hypothesize that Draxin mutations will cause both structural and behavioral deficits and predict that CC size is associated with behavioral performance and that it may serve as a marker for complex disorders. This research should lead to a better understanding of the biology underlying CC development and the subsequent effects on the social, motor and cognitive aspects of autism and other complex disorders.