PROJECT SUMMARY βII-spectrin (encoded by SPTBN1), is a ubiquitous component of the submembrane neuronal cytoskeleton. βII- spectrin binds F-actin and ankyrins to organize complex networks of ion channels, membrane transporters and cell adhesion molecules. βII-spectrin also promotes bidirectional transport of organelles and vesicles. Our lab recently reported de novo SPTBN1 variants as the genetic cause of a developmental delay syndrome that is comorbid with intellectual disability, autism spectrum disorder, ADHD, and seizures. However, the neuron types and brain circuits most vulnerable to deficits in βII-spectrin function and their specific contribution to the diverse neurological presentations are not fully elucidated. My preliminary studies indicate that βII-spectrin plays important roles in modulating cerebellar function and that cerebellar dysfunction may contribute to the SPTBN1 syndrome. To begin to unravel the roles of βII-spectrin in the cerebellum, I will focus on investigating its function in cerebellar granule cells by determining how βII-spectrin promotes: 1) the organization of excitable axonal domains and 2) axonal organelle dynamics.