Regulation of in vivo cortical circuit function and behavior by synaptic GEFs and GAPs

UF Scripps (Project 4) PROJECT SUMMARY The goal of this center is to understand how gene expression and function within neuronal subtypes regulates neurobiological substrates required to form cortical circuits that enable decision-making and behavioral adaptations. The Center will address this topic through in-depth biological investigations of Trio and Syngap1, two regulators of GTPase signaling in the brain that are also causally linked to NDDs. A defining feature of the Center is that these genes will be studied at multiple levels of neural function - molecular, cellular, synaptic, circuit, behavior. In keeping with the theme of the center, Project 4 will assess the function of these genes at the highest levels of brain function – how they regulate the functional integration of neuronal subtypes into circuits required for behavioral adaptations. Project 4 will address the unifying themes in the Center by measuring neuronal subtype functional circuit integration, circuit plasticity, and behavioral adaptions, by utilizing three classes of mouse perturbation models that target expression or function of these genes. The first set of perturbation models will assess how the cell-autonomous expression of each gene -- within unique neural subtypes and at different periods of development -- impact cortical circuit function and behaviors these circuits are known to guide. The second set of models will express point mutations within known functional domains of the proteins encoded by these genes. Finally, the third set of models will include acute and/or chronic pharmacological manipulations of Trio and Syngap1 GEF/GAP domains. The impact of this research is that it will highlight, when, where, and how these genes regulate circuit assembly and circuit plasticity required for transforming sensory signals into decisions that drive behavior.