Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders

We generated human-induced pluripotent stem cell (hiPSC) derived neurons isolated from six childhood-onset schizophrenia (COS) cases and five healthy controls. To measured the transcriptional and epigenomic changes following neuronal activation with KCl, we harvested these cells one and six hours after stimulation with 50mM KCl and under non-stimulating conditions, followed by RNA-seq and ATAC-seq profiling. We comprehensively characterized activity-dependent changes in gene expression and gene regulatory element activity (chromatin accessibility) in hiPSC-derived neurons. After one hour of KCl induced depolarization, neurons invoked substantial activity-dependent changes in the expression of genes regulating synaptic functions, some of which are known to be perturbed in neuropsychiatric diseases, including schizophrenia and autism spectrum disorder. By capturing changes in chromatin accessibility, we extended our analysis to activity-dependent gene regulatory elements, captured by changes in chromatin accessibility, and also found significant heritability enrichment for schizophrenia variants in the activity-induced enhancers. Our framework not only offers an alternative approach to study the mechanisms of COS but also adds to converging evidence that activity-induced expression changes mediated by the activity of regulatory elements might contribute to schizophrenia risk. Gene expression (RNA-seq) and open chromatin (ATAC-seq assay) profiles in hiPSC neurons in unstimulated and KCl-stimulated conditions (measured after 1hr and 6hr following membrane depolarization).