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Application of an ex vivo cellular model of circadian variation for bipolar disorder research: a proof of concept study

Authors

  • Mikhil N Bamne,

    1. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA
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    • These authors contributed equally to the paper.
  • Christine A Ponder,

    1. Laboratory of Genetics, The Rockefeller University, New York, NY
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    • These authors contributed equally to the paper.
  • Joel A Wood,

    1. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Hader Mansour,

    1. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Ellen Frank,

    1. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • David J Kupfer,

    1. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Michael W Young,

    1. Laboratory of Genetics, The Rockefeller University, New York, NY
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  • Vishwajit L Nimgaonkar

    Corresponding author
    1. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
    • Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Corresponding author:

Vishwajit L. Nimgaonkar, M.D., Ph.D.

Department of Psychiatry

Western Psychiatric Institute and Clinic

University of Pittsburgh School of Medicine

3811 O'Hara Street, Room 443

Pittsburgh, PA 15213

USA

Fax: 412-246-6350

E-mail: nimga@pitt.edu

Abstract

Objectives

Disruption of circadian function has been observed in several human disorders, including bipolar disorder (BD). Research into these disorders can be facilitated by human cellular models that evaluate external factors (zeitgebers) that impact circadian pacemaker activity. Incorporating a firefly luciferase reporter system into human fibroblasts provides a facile, bioluminescent readout that estimates circadian phase, while leaving the cells intact. We evaluated whether this system can be adapted to clinical BD research and whether it can incorporate zeitgeber challenge paradigms.

Methods

Fibroblasts from patients with bipolar I disorder (BD-I) (n = 13) and controls (n = 12) were infected ex vivo with a lentiviral reporter incorporating the promoter sequences for Bmal1, a circadian gene to drive expression of the firefly luciferase gene. Following synchronization, the bioluminescence was used to estimate period length. Phase response curves (PRCs) were also generated following forskolin challenge and the phase response patterns were characterized.

Results

Period length and PRCs could be estimated reliably from the constructs. There were no significant case-control differences in period length, with a nonsignificant trend for differences in PRCs following the phase-setting experiments.

Conclusions

An ex vivo cellular fibroblast-based model can be used to investigate circadian function in BD-I. It can be generated from specific individuals and this could usefully complement ongoing circadian clinical research.

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