title: Lithium effects on circadian rhythms in fibroblasts and suprachiasmatic nucleus slices from Cry knockout mice.
abstract: 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.
authors.affiliation: 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. Electronic address: tnoguchi@ucsd.edu.
authors.forename: Takako
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC0603, La Jolla, CA 92093-0603, USA. Electronic address: kevin.lo.1990@gmail.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lo
authors.affiliation: Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC0603, La Jolla, CA 92093-0603, USA. Electronic address: tdiemer@ucsd.edu.
authors.forename: Tanja
authors.initials: T
authors.lastname: Diemer
authors.affiliation: 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. Electronic address: welshdk@ucsd.edu.
authors.forename: David K
authors.initials: DK
authors.lastname: Welsh
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics; D056931:Cryptochromes / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D018021:Lithium Chloride / Q000009:adverse effects / Q000494:pharmacology*; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000187:drug effects* / Q000502:physiology
chemical_list: D018692:Antimanic Agents; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D018021:Lithium Chloride
keywords: Bipolar; Circadian rhythm; Cry; Lithium; PER2; Suprachiasmatic nucleus