ABSTRACT – CORE B Synaptic GEF and GAPs have emerged as significant players in neurodevelopmental disorders (NDDs). While a large number of clinical variants have been reported in these genes in patients with NDDs, their molecular and cellular consequences have not been systematically analyzed. The precise biological functions of synaptic GEF and GAP in human neuronal subtypes remain unclear, while there are no chemical tool compounds that can acutely manipulate their catalytic activity. Recent advances in the generation and differentiation of patient-specific induced pluripotent stem cells (iPSCs) offer new opportunities for elucidating the pathogenic mechanisms of NDDs. Certain unique capabilities of iPSC technologies are well suited for the study of NDDs, including providing a platform for examining the effects of genetic approaches or chemical probes on human neuron activity, morphology, and developmental processes, and enabling investigations of distinct human neuronal subtypes. Our Center proposes to study genetic variants in human synaptic GEF and GAP genes and their associated phenotypes in human iPSC-derived neurons. The overarching goal of Core B is to provide high quality, efficient and cost-effective services to Center members related to iPSC technologies. Core B will have an exclusive focus on the neurobiology of NDDs. Core B will align with the goals of Projects 1 and 2 to interrogate NDD-relevant cellular and network phenotypes. All data and cell lines generated by the Neurodevelopmental Stem Cell Core will be shared with the members of our Center and the broader academic community. The specific aims of the Neurobiology Stem Cell Core (Core B) are: 1) To generate, perform QC, expand and maintain high-quality iPSC lines. 2) To perform CRISPR mutagenesis to generate isogenic lines with high-priority missense and nonsense mutations. 3) To generate human iPSC-derived excitatory/inhibitory neuron cocultures.