Cytoskeletal pathways of cerebellar dysregulation in neurodevelopmental disorders

PROJECT SUMMARY βII-spectrin, a ubiquitous component of the neuronal cytoskeleton, plays multifaceted roles in the organization and function of neurons. We recently reported that de novo variants in SPTBN1, which encodes βII-spectrin, cause a pediatric syndrome characterized by global developmental delay, intellectual disability, ADHD, autism spectrum disorder (ASD), movement deficits, and epilepsy. However, the neuronal types and pathways that are most vulnerable to deficits in βII-spectrin function are largely unexplored. We found that mice with selective loss of βII-spectrin in cerebellar granule cells exhibit symptoms and behaviors consistent with the clinical presentations observed in individuals carrying pathogenic SPTBN1 variants. The cerebellum, previously assumed to mostly modulate fine-motor coordination, plays important roles in cognition and is suspected to contribute to the pathophysiology of neurodevelopmental diseases. Thus, it is important to define the normal and pathogenic mechanisms modulated by βII-spectrin function in the cerebellum. To accomplish these goals, we will combine cellular, biochemical, live and super-resolution microscopies, and electrophysiological techniques with behavioral paradigms to 1) determine the molecular mechanisms underlying disruption of excitable axonal domains and synaptic transmission in cerebellar granule cells caused by βII- spectrin deficiencies and 2) leverage novel transgenic mouse models carrying clinically relevant Sptbn1 variants to assess their effect on cerebellar molecular, cellular, and synaptic function and clinically relevant behaviors.