Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability

Neuronal activity-dependent gene expression is essential for brain development. While transcriptional and epigenetic effects of neuronal activity have been explored in the mouse, such an investigation is lacking in human. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell (hiPSC)-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible following membrane depolarization, some of which have specifically evolved in primates, and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters, and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk.