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L-Type Calcium Channel Cav1.2 and Circadian Rhythms in Bipolar Disorder Patient Fibroblasts

  • Author(s): Nudell, Victoria Shannon
  • Advisor(s): McCarthy, Michael J
  • Spitzer, Nicholas
  • et al.

Bipolar disorder (BD) is a psychiatric disorder characterized by recurrent periods of depression and mania, accompanied by major disruptions in activity and sleep patterns. The circadian clock controls these behavioral rhythms however; genome-wide association studies have failed to identify any of the essential “clock genes” that regulate rhythms as major genetic contributors in BD, but have associated the genes encoding L-type calcium channels (LTCCs) as important risk factors. CACNA1C encodes CaV1.2, a LTCC essential for entrainment of the circadian clock. In post mortem brain studies, those with BD risk-associated variants in CACNA1C show alterations in gene expression. However, it is not known if abnormal expression of calcium channels mediates the circadian disruptions observed in BD patients. We utilized a viral per2::luciferase reporter to measure circadian rhythms in vitro and evaluate the role of a BD-associated risk allele in CACNA1C (rs4765913) and its role in human fibroblasts during phase-shifting. We found that antagonizing ryanodine receptors lengthens period whereas, blocking LTCCs shortens of the rhythm of per2::luc expression in mouse fibroblasts. Interestingly, the period changing effects of calcium channel blockers were insignificant when applied in conjunction with a temperature cycle. CACNA1C genotype (rs4765913) predicted the ability of human fibroblasts from BD patients to entrain to temperature cycles. These findings give insight as to the role of CACNA1C genotype in the ability of fibroblasts to entrain to daily stimuli, and how the abnormal entrainment displayed in BD-associated risk allele carriers could contribute to the circadian abnormalities observed in BD patients.

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