CORE C PROJECT SUMMARY The principal goal of this Center is to understand how gene expression and associated function within key neuronal subtypes regulates neurobiological substrates required to form cortical circuits that enable decision-making and behavioral adaptations. Ras and Rho-like small GTPases play fundamental biological roles within neurons by controlling cell-autonomous growth-related signaling pathways and orchestrating neuronal circuit assembly. Consistent with the biological importance of GTPase signaling in brain development and function, several prominent neurodevelopmental disorder (NDD) risk genes are upstream regulators of neuronal small GTPase signaling. We will focus on the neurobiology of two major genetic regulators of GTPase signaling, TRIO, a top 10 risk factor for schizophrenia, and SYNGAP1, a top 10 risk factor for ASD and intellectual disability. TRIO/SYNGAP1 are molecular effectors that orchestrate neuronal migration, neuronal morphogenesis, synaptic connectivity, synaptic plasticity, in vivo neural circuit function, and associated behavioral adaptations. However, it is currently unknown how their expression and function within specific neuronal subtypes and defined developmental time windows refine cortical circuits to impact cognitive processing and associated behaviors. Our interdisciplinary, multi-institutional “Center for GTPase Regulation of Neuronal Cell Biology and Behavior” will study the contributions of TRIO/SYNGAP1 in cortical circuit assembly at cellular, synapse, circuit, systems, and behavioral levels in complementary model systems, including mouse models and human iPSC-derived neurons. The Mouse Resource Core will facilitate studies using mouse models. Mouse somatosensory cortex shares similar overall architecture and approximates human molecular pathways, neuronal function, and circuit organization. Thus, mouse models are a valuable system for studying cortical development at the level of neurons, synapses, circuits and systems, as well as for evaluating potential therapeutic strategies. The mouse genome is a tractable system for engineering mutations in orthologous genes to enable study of genetic variants in the context of brain tissue. Conditional deletion strategies allow for dissection of cell-type specific effects underlying synapse and circuit dysfunction. Combining genetic manipulation with electrophysiologic and optogenetic tools, allows for detailed, multilevel mechanistic studies in the context of an intact cortex, our Center will address gaps in knowledge about the contribution of small GTPase regulators to cortical circuit assembly. The primary objectives of the Mouse Resource Core are to provide centralized support of mouse model needs for the Center Projects, including generation of novel knock-in mouse lines; maintenance and specialized breeding of genetically modified mice; and facilitating sharing of mouse lines with the academic community. Our centralized mouse core will provide e...