Investigating the cellular and molecular neuropathology of the cerebellum in autism

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PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a common, heterogeneous diagnosis with behavioral challenges that develop early in life. The cerebellum is one part of the brain that has an important role in contributing to ASD pathogenesis, though details regarding the biological mechanisms and the emergence of atypical development is not understood. To address this significant gap in knowledge, we will examine ~100,000 individual cells to characterize the molecular and cellular phenotypes present in the cerebellum of individuals diagnosed with ASD. In Aim 1, we will use single-nucleus RNA-sequencing to identify all cell types in the postmortem cerebellum and laser capture microdissection to specifically isolate Purkinje cells from the cerebellar cortex to examine this cell type in detail. In Aim 2, we will integrate existing bulk and single-cell transcriptional datasets to infer the temporal specificity of cellular phenotypes present in the cerebellum of individuals diagnosed with ASD. By integrating new and existing data, this study will provide critical information regarding the molecular and cellular diversity of the cerebellum in ASD that can be used to elucidate the molecular mechanisms underlying ASD neuropathology.