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.

Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients

“…When considered with our previous results (McCarthy et al, 2013) and the literature, our results indicate that both the ERK1/2 pathway and GSK3B pathway are altered in BD cells and/or affected by lithium. Our previous work demonstrated that genetic variation in GSK3B is selectively associated with the amplitude response to lithium in BD patients (McCarthy et al, 2013), and selective pharmacological inhibition of GSK3B increases amplitude in a manner similar to lithium (Li et al, 2012). This suggests that both GSK3B and ERK1/2 are importantly involved in the amplitude increasing effect of lithium, with GSK3B acting at baseline to reduce baseline rhythm amplitude and ERK acting to increase it.…”

“…Between mood episodes, euthymic subjects have more variable rhythms, with less daytime activity, more nighttime activity, and reduced sleep compared to controls (Jones et al, 2005;, suggesting that rhythm disturbances are a stable trait marker of BD. The mood stabilizer lithium treats BD symptoms, and has effects on circadian rhythms in cells, including increases in amplitude (Johansson et al, 2011;Li et al, 2012;McCarthy et al, 2013). Because skin fibroblasts contain cell autonomous circadian clocks, they can be used to study rhythms and their molecular mechanisms in clinical samples, including those from BD patients (Liu et al, 2007;McCarthy et al, 2013).…”

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

“…It is of interest to contrast the period-shortening effects of VPA to the period-lengthening effects of lithium, another mood stabilizer (Li et al, 2012). The opposing effects of these two drugs on circadian rhythms might seem to imply that their circadian effects are unrelated to their mood-stabilizing effects.…”

RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response

“…38,39 Lithium, used as a treatment of mania and as prevention of bipolar disorder, inhibits glycogen synthase kinase 3b that, in turn, regulates protein stability of components of the molecular clock. 40,41 Under treatment with lithium, increased amplitudes of clock gene oscillations have been observed on the cellular and tissue level, 42 as well as increased circadian period length on the behavioral level. 42,43 Intriguingly, McCarthy et al…”