Impaired neural stress resistance and loss of REST in bipolar disorder.
Katharina MeyerKing-Hwa LingPei-Ling YeoAngeliki SpathopoulouDerek DrakeJaejoon ChoiLiviu AronMariana Garcia-CorralTak KoEunjung Alice LeeJenny M TamRoy H PerlisGeorge M ChurchLi-Huei TsaiBruce A YanknerPublished in: Molecular psychiatry (2023)
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 human cerebral organoid model of BD that exhibits altered 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 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 were 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.
Keyphrases
- bipolar disorder
- genome wide
- subarachnoid hemorrhage
- gene expression
- end stage renal disease
- major depressive disorder
- neural network
- transcription factor
- prefrontal cortex
- endothelial cells
- newly diagnosed
- single cell
- rna seq
- chronic kidney disease
- poor prognosis
- cerebral ischemia
- genome wide identification
- peritoneal dialysis
- cell proliferation
- prognostic factors
- blood brain barrier
- induced pluripotent stem cells
- brain injury