Bipolar disorder is associated with mood episodes and low amplitude circadian rhythms. Fibroblasts from bipolar disorder patients have also previously been shown to have weaker lithium-induced amplification of circadian rhythms compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels have emerged as genetic risk factors for bipolar disorder, the authors examined whether loss of function in L-type calcium channels accounts for the attenuated response to lithium in bipolar disorder cells.
Fluorescent dyes were used to measure Ca(2+) changes in bipolar disorder and control fibroblasts after lithium treatment. Bioluminescent reporters were used to measure Per2::luc rhythms in fibroblasts from bipolar disorder patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium’s ability to amplify rhythms. Additionally, independently of L-type calcium channels, lithium stimulated intracellular Ca(2+) less effectively in bipolar disorder versus control fibroblasts.
The authors concluded that calcium signaling is abnormal in cells from bipolar disorder patients, and that L-type calcium channels underlie the failure of lithium to amplify circadian rhythms.
McCarthy MJ, Le Roux MJ, Wei H, Beesley S, Kelsoe JR, Welsh DK: Calcium channel genes associated with bipolar disorder modulate lithium’s amplification of circadian rhythms. Neuropharmacology 101:439-448 (2016).