Lithium effects on circadian rhythms in fibroblasts and suprachiasmatic nucleus slices from Cry knockout mice

NEUROSCIENCE LETTERS

卷:619

Article

Noguchi, Takako^1,2,3  Lo, Kevin^1,2  Diemer, Tanja^1,2  Welsh, David K.^1,2,3 

[1] Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr MC0603, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Ctr Circadian Biol, 9500 Gilman Dr MC0603, La Jolla, CA 92093 USA

[3] Vet Affairs San Diego Healthcare Syst, 3350 La Jolla Village Dr, San Diego, CA 92161 USA

关键词: Lithium;    Cry;    PER2;    Circadian rhythm;    Suprachiasmatic nucleus;    Bipolar;   

DOI  :  10.1016/j.neulet.2016.02.030

来源: Elsevier

【 摘 要 】

Lithium is widely used as a treatment of bipolar disorder, a neuropsychiatric disorder associated with disrupted circadian rhythms. Lithium is known to lengthen period and increase amplitude of circadian rhythms. One possible pathway for these effects involves inhibition of glycogen synthase kinase-3 beta (GSK3-beta), which regulates degradation of CRY2, a canonical clock protein determining circadian period. CRY1 is also known to play important roles in regulating circadian period and phase, although there is no evidence that it is similarly phosphorylated by GSK-3 beta. In this paper, we tested the hypothesis that lithium affects circadian rhythms through CRYs. We cultured fibroblasts and slices of the suprachiasmatic nucleus (SCN), the master circadian pacemaker of the brain, from Cry1-/-, Cry2-/-, or wild-type (WT) mice bearing the PER2:LUC circadian reporter. Lithium was applied in the culture medium, and circadian rhythms of PER2 expression were measured. In WT and Cry2-/- fibroblasts, 10 mM lithium increased PER2 expression and rhythm amplitude but not period, and 1 mM lithium did not affect either period or amplitude. In non-rhythmic Cryl-/- fibroblasts, 10 mM lithium increased PER2 expression. In SCN slices, 1 mM lithium lengthened period similar to 1 h in all genotypes, but did not affect amplitude except in Cry2-/- SCN. Thus, the amplitude-enhancing effect of lithium in WT fibroblasts was unaffected by Cry2 knockout and occurred in the absence of period-lengthening, whereas the period-lengthening effect of lithium in WT SCN was unaffected by Cry1 or Cry2 knockout and occurred in the absence of rhythm amplification, suggesting that these two effects of lithium on circadian rhythms are independent of CRYs and of each other. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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