Single-Cell Genomics Unveils Cell Type-Specific Changes in Autism
Recent advancements in single-cell genomics have revealed significant insights into the molecular and cellular alterations in autism spectrum disorder (ASD). Historically, psychiatric disorders like ASD were distinguished from neurological conditions by the absence of histological pathology. However, epigenetic and transcriptional profiling of postmortem brain samples from individuals with ASD has uncovered robust molecular differences. These include up-regulation of immune signaling genes, down-regulation of neuronal markers, and altered gene expression signatures in the cortex.
A comprehensive study utilizing single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) was conducted on a large cohort, identifying 26 major cortical cell types and revealing cell states primarily activated in ASD, such as microglia, oligodendrocytes, astrocytes, and blood-brain barrier cells. Although changes in cell composition were subtle, significant gene expression changes were observed, with 2166 down-regulated and 1319 up-regulated genes across 35 cell types, predominantly cell type-specific.
By integrating snRNA-seq, snATAC-seq, and spatial transcriptomics, the study identified regulatory networks driving these cell type-specific transcriptional changes and their localization within cortical laminae. Notably, activated microglia, astrocytes, and somatostatin interneurons concentrated in superficial cortical layers, alongside down-regulation of synaptic genes and up-regulation of stress-response and pro-inflammatory pathways in projection neurons. These findings highlight the connection between autism genetic susceptibility and molecular and cellular alterations in the brain, providing a framework for understanding cellular interactions and developing targeted therapies for ASD.
