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

Oct 24, 2013Translational psychiatry

Genetic and clinical factors predict lithium's influence on daily rhythms of a key gene in cells from bipolar disorder patients

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Abstract

Lithium (Li) increased rhythm amplitude by 36% in healthy controls but not in bipolar disorder (BD) patients.

Bipolar disorder is associated with longer baseline circadian periods compared to healthy controls.
Lithium at 1 mM improved rhythm amplitude in healthy controls but failed to do so in BD patients.
Lithium at 10 mM lengthened circadian period in both BD patients and healthy controls.
Variations in clock genes PER3 and RORA were linked to period lengthening by lithium, while GSK3β variation specifically affected BD patients.
BD patients with a history of suicide attempts showed a greater likelihood of period lengthening in response to lithium at 1 mM.
Lithium also facilitated the resynchronization of damped circadian rhythms, indicating a potential therapeutic mechanism for bipolar disorder.

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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.

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

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