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Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies

Molecular Psychiatry volume 26, pages 3383–3394 (2021)Cite this article

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Abstract

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

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Fig. 1: Generation of human neurons from induced pluripotent stem cells.
Fig. 2: Luminometer assays of circadian rhythms in NPC and neurons.
Fig. 3: Single-cell assays of circadian rhythms in NPC and neurons.
Fig. 4: Circadian clock gene expression in NPCs and neurons.
Fig. 5: Effects of lithium and temperature entrainment on neuronal rhythms.

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Acknowledgements

The authors wish to thank Anna Nilsson, Lucia Illescas, Rita Fischer, for technical assistance; and Carol Marchetto and Krishna Vadodaria for helpful input. The work was funded by VA Merit Awards to MJM (BX003431) and DKW (BX001146) and a Catalyst Research Award from the International Bipolar Foundation to MJM. Sample collection and clinical assessment in the PGBD Trial was supported by NIMH/NIGMS (MH92758), The Western Norway Regional Health Authority and the Canadian Institutes of Health Research (#64410).

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Authors and Affiliations

  1. VA San Diego Healthcare System, San Diego, CA, USA

    Himanshu K. Mishra, Heather Wei, Caroline M. Nievergelt, John R. Kelsoe, David K. Welsh & Michael J. McCarthy

  2. Department of Psychiatry and Center for Circadian Biology, University of California San Diego, La Jolla, CA, USA

    Himanshu K. Mishra, Noelle M. Ying, Angelica Luis, Heather Wei, Metta Nguyen, Timothy Nakhla, Sara Vandenburgh, Caroline M. Nievergelt, Paul D. Shilling, John R. Kelsoe, David K. Welsh & Michael J. McCarthy

  3. Department of Psychiatry, Dalhousie University Halifax, Halifax, NS, Canada

    Martin Alda

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

    Wade H. Berrettini

  5. Departments of Neuroscience and Psychiatry, Icahn School of Medicine at Mt Sinai, New York, NY, USA

    Kristen J. Brennand

  6. Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA

    Joseph R. Calabrese

  7. Department of Psychiatry, University of Iowa, Iowa City, IA, USA

    William H. Coryell

  8. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    Mark A. Frye

  9. Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA

    Fred H. Gage

  10. Department of Psychiatry, University of Chicago, Chicago, IL, USA

    Elliot S. Gershon

  11. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    Melvin G. McInnis

  12. Department of Psychiatry, Indiana University, Indianapolis, IN, USA

    John I. Nurnberger

  13. Section for Psychiatry, University of Bergen and Norment and KG Jebsen Centre for Neuropsychiatry, Division of Psychiatry Haukeland University Hospital, Bergen, Norway

    Ketil J. Oedegaard

  14. Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA

    Peter P. Zandi

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Mishra, H.K., Ying, N.M., Luis, A. et al. Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies. Mol Psychiatry 26, 3383–3394 (2021). https://doi.org/10.1038/s41380-021-01048-7

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