Autism-relevant oxysterol signaling regulates GABAergic neurogenesis and interneuron subtype specification

Abstract Disturbances in GABAergic neurodevelopment are thought to underlie cortical network dysfunction in neurodevelopmental disorders (NDDs) such as autism and schizophrenia. The diversity of GABAergic neurons is shaped by cortical cues during prolonged postmitotic differentiation, yet how pathological environments associated with NDDs influence this process remains poorly understood. Oxysterols, oxidized cholesterol metabolites or its precursors, modulate key developmental signaling pathways. Here, using an iPSC-based model of human forebrain GABAergic neuron differentiation combined with single-cell transcriptomics, we show that 24S,25-epoxycholesterol, an oxysterol enriched in the fetal brain and dysregulated in NDDs, enhances neurogenesis while altering the distribution of GABAergic neuronal subtypes. Pharmacological and genetic perturbations further identify the liver X receptor as a critical mediator of these effects. Together, these findings uncover a link between cholesterol metabolism and GABAergic fate specification, suggesting that aberrant oxysterol signaling contributes to the pathogenesis of NDDs.