Impaired communication between neurons, or synaptic transmission, is thought to underlie autism-associated behaviors. The goal of this research project is to identify specific deficits in synaptic transmission as novel targets for future therapy. Shank3 is a postsynaptic scaffolding protein required for normal synapse maturation and function, and mutations and copy number variations in the Shank3 gene have been directly implicated in heritable autism with mental retardation in humans. Our laboratory will use genetic mouse models of autism containing regional deletions of the Shank3 gene to 1) Understand how the structure and function of hippocampal synapses are impaired by region-specific mutations in the Shank3 gene, and 2) Determine if each mutation contributes to autism-associated deficits in learning and memory. This thorough, interdisciplinary strategy will identify subcellular mechanisms that will immediately translate into pre-clinical studies for treatment of autism-associated behavioral deficits.