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Assessment of circadian function in fibroblasts of patients with bipolar disorder

Molecular Psychiatry volume 14, pages 143–155 (2009)Cite this article

Abstract

Previous studies have implicated the circadian system in the pathophysiology of bipolar disorder, but conclusive evidence for altered circadian clocks is lacking. Cultured fibroblasts harbor circadian clocks representative of those in the master clock resident in the suprachiasmatic nuclei, providing a new avenue to investigate the core clock machinery in patients with bipolar illness. We examined the rhythmic expression patterns of core clock genes (BMAL1, PER1, PER2, REV-ERBα, DEC2, DBP) in fibroblasts from 12 bipolar patients and 12 healthy controls. Although we did not detect differences in the circadian period between bipolar patients and controls, the amplitude of rhythmic expression for BMAL1, REV-ERBα and DBP, as well as the overall mRNA expression level for DEC2 and DBP was reduced in fibroblasts from bipolar patients. Bonferroni's correction for multiple comparisons still resulted in significantly reduced DBP expression level, and trends toward reduced overall expression level of DEC2 and circadian amplitude of BMAL1, in fibroblasts from bipolar patients. We next examined an expanded cohort of 18 bipolar patients and 35 healthy controls for mRNA expression levels of four kinases (CKIδ, CKIɛ, GSK3α and GSK3β) and the protein and phosphorylation levels of two of them (GSK3α and GSK3β). We did not detect differences in steady-state mRNA levels or protein levels of these kinases between bipolar patients and controls, but the level of GSK3β phosphorylation was significantly reduced in bipolar patients within an Old Order Amish bipolar kindred. Our results suggest that the reduced amplitudes and overall expression levels of circadian genes, and the decreased phosphorylation level of GSK3β may lead to dysregulation of downstream genes, which could explain some pathological features of bipolar disorder.

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Acknowledgements

We thank Janice Egeland at the Department of Psychiatry and Behavioral Sciences, University of Miami North Research Office, Hershey, PA, for sharing with us the updated diagnosis of Bipolar patients; Junhyong Kim for his advice and help with the analysis; Amita Sehgal and JD Alvarez for their advice in setting up the fibroblast culture experiment and helpful discussion; John Rinn and Howard Chang for sharing their unpublished results; John B Hogenesch, Peter Klein and Timothy O’Brien for their insightful advice and critical reading of the manuscript; and Michael Farias, Chris Weber, Rui Liu and Jessica Ardis for their technical help. This work was supported by the NIH (R01 MH604687; R21 MH078179) and, in part, by a grant from the Pennsylvania Department of Health. Hans Van Dongen was supported by congressionally directed funding W81XWH05-1-0099 through the US Army Medical Research and Materiel Command.

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  1. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA

    S Yang, K Wang & M Bućan

  2. Sleep and Performance Research Center, Washington State University, Spokane, WA, USA

    H P A Van Dongen

  3. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    W Berrettini

  4. Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, PA, USA

    M Bućan

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Yang, S., Van Dongen, H., Wang, K. et al. Assessment of circadian function in fibroblasts of patients with bipolar disorder. Mol Psychiatry 14, 143–155 (2009). https://doi.org/10.1038/mp.2008.10

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