REST and Impaired Neural Stress Resistance in Bipolar Disorder

Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a cerebral organoid model of BD that exhibits altered early neural development, elevated neural network activity, and a major shift in the transcriptome. These phenotypic changes were reproduced in cerebral organoids generated from iPS cell lines derived in multiple different laboratories. The BD cerebral organoid transcriptome showed highly significant enrichment for gene targets of the transcriptional repressor REST. This was associated with reduced nuclear REST and REST binding to target gene recognition sites. Reducing the oxygen concentration in organoid cultures to a physiological range ameliorated the developmental phenotype and restored REST expression. These effects were mimicked by treatment with lithium. Reduced nuclear REST and derepression of REST targets genes was also observed in the prefrontal cortex of BD patients. Thus, an impaired cellular stress response in BD cerebral organoids leads to altered neural development and transcriptional dysregulation associated with downregulation of REST. These findings provide a new model and conceptual framework for exploring the molecular basis of BD Overall design: The aim of this study was to establish a cerebral organoid model of BD to identify and study disease relevant phenotypes. We performed unbiased RNA sequencing (RNAseq) analysis and analyzed overall structure and morphology of cerebral organoids. Sample size was not calculated prior to experiments. Initial experiments were performed on 5 control and 7 bipolar disorder iPSC lines and later reproduced in additional 5 controls and 5 bipolar disorder iPSCs from different sources. All experiments were repeated 3-5 times by seeding and growing several batches of cerebral organoids from all available lines. Outliers were determined by first, gross morphological observation of organoids, as some lines randomly do not produce viable organoids in each batch and second, by statistical ROUT analysis.