Little is known about the changes in the brain that occur in human autism spectrum disorder (ASD). To allow researchers from different fields to conduct research studies on molecular pathogenesis of ASD, a valid animal model of ASD supported by genetic evidence is clearly needed. Multiple independent studies report mutations in the SHANK3 gene in a small, but significant, set of individuals with ASD. SHANK3 functions as a master scaffolding protein in the deep layer of postsynaptic density, an important structure for development and function of the synapse of neurons. Thus, studying the SHANK3 gene in mice will potentially be the best animal model of ASD. Dr. Jiang's laboratory created the first 'knockout' mouse which deleted the SHANK3 gene in mice. The preliminary studies of these mice indicate that several important proteins at synapses are altered and learning and memory are impaired. These data strongly support the extensive exploration of SHANK3 knockout mice as an ASD model. The research team will dissect the SHANK3 protein network, assess synaptic structure and function, and evaluate behavioral changes in this ASD animal model. Future studies may lead to important insights into the synaptic basis of ASD pathogenesis and to explore novel therapeutic strategies for ASD. Previously, this investigator used a similar approach to successfully characterize a mouse model of Angelman syndrome. He has assembled an outstanding research team with collaborators at Duke and the University of North Carolina. Results from this study may elucidate the role of SHANK3 in synaptic function and, more importantly, produce a valid mouse model to dissect the pathogenesis of ASD using cutting-edge neurobiological and neuroimaging techniques in future.