PROJECT SUMMARY The candidate is a tenure-track assistant professor at James Madison University, with the overarching goal of understanding the development of the structure and function of the cerebral cortex to better diagnose and treat neurodevelopmental disorders. His long-term research objective is to clarify the developmental and cell- specific roles of integrins in the brain, and the overall focus of his proposal is to advance this objective by understanding the developmental, anatomical, physiological, and behavioral roles of integrin beta 3 (Itgb3) in excitatory cortical circuitry in vivo. His professional goals are to establish research independence and create a network of outstanding colleagues. Achieving these goals will also strengthen his research program in a NINDS-relevant area to compete successfully for R01/R15 funding by year 3 of the award and achieve tenure. A team of outstanding, NIH-funded mentors will guide the candidate toward the stated goals. The primary mentor is Dr. Mark Gabriele (James Madison Univ.), an expert in developmental neurobiology. The three co- mentors are neuroscientists Dr. Jonathan Kipnis (UVA), an expert in autism and neuroimmunology, Dr. Patricia Maness (UNC), an expert in cell adhesion molecules associated with neurodevelopmental disorders, and Dr. Gregorio Valdez (Virginia Tech), a recent NINDS K01 awardee who has since secured an R01 and tenure. The candidate has the full support of his colleagues (Career Advisory Committee) and institution. The overall goal of the proposed research is to understand the developmental role of Itgb3 in excitatory cortical circuitry in vivo and establish a framework linking the anatomical, physiological, and behavioral consequences of Itgb3 loss of function. The central hypothesis is that Itgb3 is required during a critical period for restricting dendritic development in pyramidal neurons, establishing a normal excitatory tone required in prefrontal cortex for normal social behavior. Preliminary data support this hypothesis, which will be tested by pursuing 3 aims: (Aim 1) Determine if Itgb3 mediates dendritic development within excitatory cortical pyramidal neurons, establishing a neural substrate for normal social behavior in prefrontal cortex. (Aim 2) Define a critical period for Itgb3 function in excitatory cortical pyramidal neurons of prefrontal cortex. (Aim 3) Define synaptic functions of Itgb3 in excitatory cortical pyramidal neurons of prefrontal cortex. This contribution is significant because it will be the first to provide a mechanism for in vivo neuronal function of integrin beta 3. The research is innovative because it shifts current research toward the neuron- and cortex- specific functions of Itgb3 by causing cell-type-specific loss of function of Itgb3 in vivo during development. Taken together, the candidate has the full support of his mentors and institution as he executes a research and career plan that will lead him toward his goals of uncovering a role for integrin beta 3 in cortical development, and of establishing an active research program that will uncover fundamental knowledge about the brain and nervous system to reduce the burden of neurodevelopmental disorders such as autism.

PROJECT NARRATIVE The proposed research is relevant to public health as it focuses on the function of genes related to autism spectrum disorder, which affects over 1 in 59 American children. The purpose of this study is to understand how integrin beta 3, an autism susceptibility gene, is necessary for the proper formation of brain circuits. Therefore, this research will provide fundamental knowledge about the brain that will inform new strategies for treating autism spectrum disorder and other neurodevelopmental disorders.