Single-nucleus RNA sequencing of post-mortem brain tissue from Autism Spectrum Disorder patients

Autism spectrum disorder (ASD), affecting 1 of 68 children in the US, is heterogeneous in terms of its clinical manifestation and associated genetic contributions. The prefrontal cortex and the limbic system are involved in higher-order cognitive functions, processing of social information, emotions and empathy. Changes in cytoarchitecture and dysfunction of these systems has been consistently reported in ASD patients. Although bulk transcriptomic studies of post-mortem tissue from patients with ASD have revealed convergence of disease pathology on common pathways1--including splicing of neuronal genes4, synaptic signaling, microglial and astrocyte reactivity—the cortical cell type-specific molecular pathologies of ASD are unclear. Here we utilized high-throughput single-nucleus RNA sequencing (snRNA-seq) of snap-frozen post-mortem brain tissue of patients with ASD compared with neurologically normal children and young adults to identify the most prominent ASD-associated molecular changes across three cortical regions. Our findings show that synaptic signaling of upper-layer excitatory neurons is especially affected in ASD. Moreover, we found significant dysregulation of grey matter astrocytes-encoded genes for glutamate uptake and modulation of synaptic plasticity. Together, these findings demonstrate molecular pathology of upper-layer cortical neuronal circuitry components and astroglia-neuronal interactions, shedding light on cellular mechanisms of ASD

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