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

GABAergic neuron diversity is sculptured by cortical environmental cues during protracted postmitotic differentiation. However, the mechanism by which NDD environments influence GABAergic neuronal development remains largely unknown.

Oxysterols are oxidized metabolites of cholesterol that can interact with developmental signaling pathways. Using an iPSC model recapitulating human forebrain GABAergic neuron development and single-cell transcriptomic profiling, we show that 24S, 25-epoxysterol, an NDD-associated oxysterol highly enriched in the fetal brain, promotes neurogenesis and disturbs the composition of neuronal subtypes. Moreover, pharmacological and genetic interrogation identified the liver X receptor as a regulatory pathway mediating the action of 24S, 25-epoxysterol.