Unraveling the Dynamic Role of Purkinje Cell Neurotransmission in Neurodevelopment.

Neurodevelopmental disability arising from prematurity poses a large and increasing disease burden and has increasingly been associated with cerebellar pathogenesis. Cerebellar development coincides with a critical developmental period during which establishment of brain networks supports neurotypical outcomes. However, the precise role of the cerebellum in supporting network structure and function through early development is poorly understood. Developing interventions to prevent and treat neurodevelopmental disability associated with associated with prematurity requires a comprehensive understanding of the dynamic circuit response to functional perturbations. This proposal uses unique features of mouse development in combination with the sophistication of mouse genetic manipulations to dynamically alter cerebellar function through a critical developmental window while comprehensively characterizing the resulting anatomic, physiologic, and behavioral disruptions of the associated networks. The central hypothesis of this proposal is that cerebellar function is first required for structural establishment of brain networks while subsequently being important for ongoing function, a dynamic that underlies the spectrum of neurodevelopmental disability. This proposal will take advantage of a model for inducible silencing of Purkinje cell neurotransmission developed by the candidate. In Aim 1, the experiments will test how early vs late cerebellar disruption affects behavior, predicting that early silencing will have pervasive behavioral deficits while late silencing will produce domain specific functional deficits. In Aim 2, the experiments are designed to examine how early vs late silencing affects the assembly and function of brain circuits using anatomic and electrophysiologic analyses. With these aims, the proposal outlines a rigorous approach that combines dynamic genetic perturbations, quantitative anatomic and electrophysiologic analyses, and cross-domain behavioral assays to better understand how early cerebellar insult contributes to neurodevelopmental disability. The candidate is a trained pediatric neurologist with extensive clinical exposure to diagnosis and treatment of neurodevelopmental disorders, application and analysis of basic and advanced imaging techniques, and research experience in model organism behavioral assays. This proposal is mentored by Dr. Roy Sillitoe, a leader in cerebellar neuroscience who has strong track record of NIH funding, mentorship, and scientific leadership. All experiments will be conducted at the Neurologic Research Institute, a pediatric neurology research facility that draws on the clinical excellence of Texas Children’s Hospital and the world-class neuroscience of Baylor College of Medicine. The professional development and training plan is designed to poise the candidate for a career as a physician scientist focused on the prevention and treatment of neurodevelopmental disability in the pediatric population specifically utilizing a gap based approach that incorporates training in network analysis and advanced statistical techniques. The completion of the entailed aims will elucidate the mechanisms by which cerebellar disruptions contribute to neurodevelopmental disability.