Genetic and clinical factors predict lithium’s effects on PER2 gene expression rhythms in cells from bipolar disorder patients

M J Mccarthy,B M Cohen,D K Welsh,D L Mcphie,R M Darvish,Z Marnoy,H Wei

doi:10.1038/tp.2013.90

Abstract

Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of ‘clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.

Highlights

Bipolar disorder (BD) is a psychiatric illness characterized by disabling episodes of depression and mania that greatly increase the risk of suicide.[1]
We investigated whether clock gene variants and clinical subtypes of BD were associated with differences in rhythms
We have shown in fibroblasts from BD patients that the cellular clock is functional, but generally runs slow, with a longer period, and is less sensitive to Li modulation

Summary

Introduction

Bipolar disorder (BD) is a psychiatric illness characterized by disabling episodes of depression and mania that greatly increase the risk of suicide.[1] The biological origins of BD are poorly characterized, but heritability is estimated to be 0.85, suggesting a genetic etiology.[2]. In the forebrain, NPAS2 may substitute for CLOCK.[5,6] Secondary loops (e.g. RORA/B/C, REV-ERBa), and posttranslational modifications by casein kinases 1d/e (encoded from CSNK1D/E) and glycogen synthase kinase 3b (GSK3b) regulate core loop functions, through alterations in protein stability and nuclear compartmentalization.[7] inhibition of GSK3b increases amplitude and shortens period of gene expression rhythms.[8,9,10]

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