Autism spectrum disorder (ASD) is a heterogeneous group of related behavioral disorders, characterized by deficits in three core domains: communication, social interaction, and repetitive behaviors. This project seeks to learn how Ube3a, a gene within the most common genetic copy number variant (CNV) found in ASD (maternal 15q11-13 duplication) affects the expression of other genes and their proteins to alter brain circuit functions underlying these behavioral disturbances. Recently, it has been found that that increasing Ube3a gene dosage alone reconstitutes the triad of autism-related behavioral deficits in mice. Thus it is hypothesized that excess Ube3a (15q duplication model) acts to perturb normal expression of specific neuronal genes and encoded proteins to alter circuit function and thereby generate autism-related behavioral deficits. This project will compare and contrast the defects in neuronal gene expression and circuit functions produced by altered Ube3a gene dosage that may underlie the behavioral phenotypes of ASD with maternal 15q11-13 duplication and Angelman's Syndrome (AS). This analysis will facilitate our efforts to bridge genes to circuits to behavior in the two contrasting human neurological diseases. The project promotes the agency's mission to further a deeper understanding of the neuronal cells, circuits, and genes involved in ASD and AS via genetic models. The novel molecular insights and genetic tools will facilitate development of therapeutic targets for these life-long behavioral disabilities.