Scn2adeletion disrupts oligodendroglia function: Implication for myelination, neural circuitry, and auditory hypersensitivity in ASD

Abstract

AbstractAutism spectrum disorder (ASD) is characterized by a complex etiology, with genetic determinants significantly influencing its manifestation. Among these, theScn2agene emerges as a pivotal player, crucially involved in both glial and neuronal functionality. This study elucidates the underexplored roles ofScn2ain oligodendrocytes, and its subsequent impact on myelination and auditory neural processes. The results reveal a nuanced interplay between oligodendrocytes and axons, whereScn2adeletion causes alterations in the intricate process of myelination. This disruption, in turn, instigates changes in axonal properties and neuronal activities at the single cell level. Furthermore, oligodendrocyte-specificScn2adeletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity—a common sensory abnormality observed in ASD. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes, highlighting the cellular consequences engendered byScn2adeletion. In summary, the findings provide unprecedented insights into the pathway fromScn2adeletion in oligodendrocytes to sensory abnormalities in ASD, underscoring the integral role ofScn2a-mediated myelination in auditory responses. This research thereby provides novel insights into the intricate tapestry of genetic and cellular interactions inherent in ASD.