UC San Diego

Bipolar Disorder is a serious neuropsychiatric disorder that causes impairment in mood regulation. Patients with Bipolar Disorder have structural brain atrophy, reduced hippocampal volume, and suffer from disturbances in circadian rhythms. The mood- stabilizer lithium is a mainstream treatment for the disorder, and has been shown to increase hippocampal gray matter volume in MRI studies. However, the mechanism of this neuroprotective effect is unclear. Lithium is also known to amplify circadian rhythms. Therefore, we sought to investigate whether modulation of circadian rhythm amplitude by molecular or pharmacological means impacts neuronal survival. Using an immortalized hippocampal cell line, we performed bioluminescent reporter assays of Per2 expression to find drugs that impacted rhythm amplitude, and ran viability assays in parallel to determine the effect of the drug on neuronal survival. We report, with lithium, verapamil, and a small sample of drugs targeting the clock genes REV-ERBα and RORα, that those that increase rhythm amplitude tend to promote neuronal survival. Conversely, we have seen that drugs that decrease rhythm amplitude tend to decrease survival. However, Bmal1 knockdown reduced amplitude but increased neuronal survival. The data suggest that there is overlap between circadian rhythm and cell survival systems, but that the relationship is not simple. Non- specific drug effects may complicate the interpretation of some results. Further studies are needed to clarify the connection.