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Several autism spectrum disorders have been linked to dysfunction of a single gene – UBE3A. Individuals having deletions or mutations of the maternal UBE3A gene suffer from the severe intellectual disability Angelman syndrome (AS), an autism spectrum disorder, while individuals expressing two or more copies of maternal UBE3A exhibit a more classic form of autism. Thus, a major goal has been to identify mechanisms for adjusting UBE3A gene dosage, as this could be of therapeutic value. UBE3A is a relatively unique gene, in that the paternally-inherited copy is silent in most brain neurons. Thus, one therapeutic opportunity for AS is to "awaken" the dormant paternal allele. The research team has recently made the exciting discovery of small molecule compounds that can unsilence paternal Ube3a in a mouse model of AS.

This study will take advantage of the well characterized synaptic deficits in AS model mice to test the therapeutic value of the lead compound. Loss of Ube3a expression has previously been shown to decrease the number of dendritic spines (synaptic sites) in the brain and alter the capacity for functional synaptic plasticity. The hypothesis that pharmacological unsilencing of paternal Ube3a will recover functional and structural plasticity of synapses in AS model mice during critical periods of brain development will be tested in this study. To date, nothing is known about the effect of unsilencing imprinted genes and whether this is a valuable therapeutic option. By filling this gap in knowledge, my studies will begin therapeutic testing of UNCilencer1, helping to lead the way into human clinical trials. These studies will afford the Fellow the opportunity to learn several new techniques, including in vivo, high-resolution microscopy combined with pharmacological manipulations. In addition to the basic science that will be performed, the Fellow will be attending, contributing, and learning from AS and drug trial patient clinics. The studies and training plan will allow the Fellow to better bridge the gap between the animal model testing and application to human patients. Ultimately this cross-disciplinary training will lead to a career that is both highly collaborative and highly translational, with a focus on developing autism therapeutics.