title: Lithium impacts on the amplitude and period of the molecular circadian clockwork.
abstract: Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Lu
authors.forename: Stephen
authors.initials: S
authors.lastname: Beesley
authors.forename: Andrew S I
authors.initials: AS
authors.lastname: Loudon
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D057906:Circadian Clocks / Q000187:drug effects* / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D008094:Lithium / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D008156:Luciferases / Q000378:metabolism; D008163:Luminescent Measurements; D008168:Lung / Q000187:drug effects / Q000502:physiology; D051379:Mice; D056950:Period Circadian Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D017931:DNA Primers; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D008094:Lithium; D008156:Luciferases; D038362:Glycogen Synthase Kinase 3