UC San Diego

Bipolar disorder (BD) is a neuropsychiatric disorder that causes depressive and manic mood episodes and greatly increases the risk of suicide. People affected by BD are known to possess circadian rhythm abnormalities, and while it has been suggested that these alterations in circadian rhythms are correlated to the symptomatic mood episodes, it is unknown how these disruptions are caused or how they specifically relate to the pathogenesis of BD. To investigate the molecular mechanisms of circadian rhythms in BD, we analyzed the circadian gene expression patterns in induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and neurons from BD subjects compared to healthy subjects. Gene expression was measured across a 24-hour cycle by performing qRT-PCR on the core clock genes that control the transcriptional-translational negative feedback loop (TTFL). Expression of two clock genes in particular, CRY1 and PER2, was found to be highly expressed in BD NPCs compared to control NPCs, demonstrating that disruption of the clock may begin early on in neuronal development. Further gene expression analyses of differentiated neurons revealed that this CRY1 and PER2 finding was consistent across cell types. No other clock genes were found to have expression differences in either cell types, demonstrating some degree of specificity regarding CRY1 and PER2’s association with BD. Our analysis shows that looking into the mechanisms of circadian gene regulation in BD is a promising area of study in uncovering the molecular workings and developmental manifestation of BD.