Modelling Neuronal Circadian Rhythms in Bipolar Disorder Using Human Induced Pluripotent Stem Cells

Bipolar Disorder (BD) is a lifelong mental disorder characterized by recurrent episodes of mania and depression. Manic episodes involve elevated mood and reduced need for sleep, while depressive episodes are associated with low energy, increased/decreased sleep, and anhedonia. As such, clinical studies have shown that BD patients experience disturbed circadian rhythms. BD is heritable, as is clinical response to the first-line mood stabilizer lithium, suggesting that a biological approach to the etiology of the disorder may provide insight to BD diagnosis and treatment. Previous research in BD patient-derived fibroblasts indicates that circadian rhythm disturbances extend to the molecular level, but the relationship between BD and the cell-autonomous molecular circadian clock remains to be clarified in the most disease-relevant cell type, neurons. Using human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) and cortex-like glutamatergic neurons, we measured the oscillatory activity of the molecular circadian clock using a lentiviral Period2-luciferase (Per2-luc) reporter. We found that BD-associated dysregulation of the molecular clock affects NPCs. In differentiated neurons, BD Li Non-Responder (Li-NR)-derived cells were found to have circadian rhythms not modulated by lithium treatment, and were more phase-dispersed and more resistant to external entrainment factors than were BD Li Responder (Li-R) and healthy control cells. We developed a temperature-entrainment protocol that successfully induced high-amplitude, 24-hour circadian rhythms in neurons from all diagnosis groups, reversing the low-amplitude phenotype in Li-NR neurons. Further characterization of the molecular circadian rhythms of BD hiPSC-derived neurons has the potential to reveal clinically-relevant indicators of BD lithium response