Noguchi Takako, Lo Kevin, Diemer Tanja, Welsh David K
Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC0603, La Jolla, CA 92093-0603, USA; Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC0603, La Jolla, CA 92093-0603, USA.
Neurosci Lett. 2016 Apr 21;619:49-53. doi: 10.1016/j.neulet.2016.02.030. Epub 2016 Feb 27.
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-3β (GSK-3β), 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-3β. 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, 10mM lithium increased PER2 expression and rhythm amplitude but not period, and 1mM lithium did not affect either period or amplitude. In non-rhythmic Cry1-/- fibroblasts, 10mM lithium increased PER2 expression. In SCN slices, 1mM lithium lengthened period ∼1h 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.
锂被广泛用于治疗双相情感障碍，这是一种与昼夜节律紊乱相关的神经精神疾病。已知锂可延长昼夜节律的周期并增加其振幅。这些作用的一种可能途径涉及抑制糖原合酶激酶-3β（GSK-3β），该酶调节CRY2的降解，CRY2是一种决定昼夜周期的典型生物钟蛋白。虽然没有证据表明CRY1同样被GSK-3β磷酸化，但已知它在调节昼夜周期和相位方面也发挥着重要作用。在本文中，我们测试了锂通过CRYs影响昼夜节律的假说。我们培养了来自携带PER2:LUC昼夜节律报告基因的Cry1-/-、Cry2-/-或野生型（WT）小鼠的成纤维细胞和视交叉上核（SCN）切片，SCN是大脑的主要昼夜起搏器。在培养基中加入锂，并测量PER2表达的昼夜节律。在WT和成纤维细胞中，10mM锂增加了PER2表达和节律振幅，但未改变周期，而1mM锂对周期和振幅均无影响。在无节律的Cry1-/-成纤维细胞中，10mM锂增加了PER2表达。在SCN切片中，1mM锂在所有基因型中均使周期延长约1小时，但除了Cry2-/- SCN外，对振幅没有影响。因此，锂在WT成纤维细胞中的振幅增强作用不受Cry2基因敲除的影响，且在没有周期延长的情况下发生，而锂在WT SCN中的周期延长作用不受Cry1或Cry2基因敲除的影响，且在没有节律放大的情况下发生，这表明锂对昼夜节律的这两种作用独立于CRYs且相互独立。
