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Preclinical therapeutic target validation of glutamate receptors in Shank3 models of autism.

State/Province Full: 
United States

This research project aims to use mouse models of human autism to validate candidate drug targets for the treatment autism associated atypical behaviors. Human mutations in three different regions of the Shank3 gene have been linked to autism, and mice with any of these mutations exhibit social interaction deficits and impaired cell-to-cell communication, termed synaptic transmission. Each mouse model also exhibits additional atypical behaviors analogous to the symptoms of autism and possesses corresponding synaptic abnormalities. The investigators have identified two mechanisms of abnormal brain function in one of these autism models that may lead directly to novel treatment for this form of autism. The research fellow will test the ability of known drugs to reverse behavioral abnormalities in this model. One target will be metabotropic glutamate receptors, a target popularized for Fragile X mental retardation syndrome. Another target will be NMDA receptors using a drug that is already FDA approved for use in humans. Additional studies will determine whether these novel treatment targets are also valid in additional mouse models of autism based on other Shank3 mutations. Validation of such treatment targets and preclinical demonstration that such treatments work in animal models of autism. This has the potential to the foundation for translation to treatments for children with autism. The training program ranges from basic biological abnormalities in the brains of mouse models of autism, to preclinical treatment trials to reverse autism-like symptoms in the mouse models, to observation of children and adults with autism in the clinical setting, including diagnosis, treatment, and clinical research.