Genetic studies indicate that SHANK3, an ASD causative gene encoding a scaffolding protein at the postsynaptic density represents one of the best opportunities to dissect the pathophysiology of ASD. Studies of various isoform-specific Shank3 knockout (KO) mice support these mice as valid models. These studies also suggest that brain regions may differentially contribute to the expression of ASD-related behaviors. However, because existing Shank3 mutant mice are not brain region-specific and not complete KO, meaning that only some Shank3 isoforms are missing and the mutation is throughout the whole brain, causality between different brain regions and ASD-like behaviors cannot be firmly established without a new mouse model. The long term goal of this project is to define anatomic regions implicated in behavioral manifestations of ASD. This will illuminate potential regions, circuits, and signaling pathways to focus development of potential treatments. The central hypothesis is that deficiency of all Shank3 isoforms in the principle cells of cortex/hippocampus versus the principle cells of the striatum will contribute to different core ASD-like behaviors.