This is an NIH Pathway to Independence Award, which provides an opportunity for promising postdoctoral scientists to transition from mentored to independent research support. The goal of this project is to identify biological phenotypes of neurons derived from induced pluripotent stem (iPS) cells from individuals with autism and defined genetic alterations in the SHANK3 gene. Many lines of evidence suggest genetic etiologies for ASDs, but little is known about the cellular/physiological ramifications of these genetic defects. Thus, to probe the cellular basis underlying autism phenotypes, the researcher will differentiate iPS cells from genetically defined ASD patients with point mutations or deletions in SHANK3 into neurons and characterize them. Genetic alterations in SHANK3 may cause defects in the intrinsic properties and synaptic function of iPS-derived neurons from these patients. The neuronal properties of these cell lines will be investigated to provide a possible mechanistic link between the genetic alterations in the patients and their behavioral phenotypes. Therapeutic strategies will also be tested by using viral-mediated gene transduction to rescue neuronal phenotypes. These experiments will contribute to understanding of mechanisms underlying autism and may lead to advances in identifying new therapeutic targets and treatment strategies. They will also lay the foundation for the development of a cell-based assay system to study iPS cells and neurons from patients with a broad set of autism spectrum disorders.