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Mol Neuropsychiatry. 2019 Apr;5(2):115-124. doi: 10.1159/000497354. Epub 2019 Apr 4.

Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels.

Author information

1
Department of Psychiatry and Center for Circadian Biology, University of California San Diego, La Jolla, California, USA.
2
VA San Diego Healthcare System Psychiatry Service, San Diego, California, USA.
3
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
4
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
5
Departments of Neuroscience and Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, New York, USA.
6
Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA.
7
Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA.
8
Department of Psychiatry, University of Connecticut, Farmington, Connecticut, USA.
9
Department of Psychiatry, Mayo Clinic, Rochester, Minnesota, USA.
10
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California, USA.
11
Department of Psychiatry, University of Chicago, Chicago, Illinois, USA.
12
Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA.
13
Department of Psychiatry, Indiana University, Indianapolis, Indiana, USA.
14
Section for Psychiatry, University of Bergen and NORMENT and KG Jebsen Centre for Neuropsychiatry, Bergen, Norway.
15
Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
16
Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA.

Abstract

Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is involved in -circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs. Using Per2-luc, a bioluminescent reporter, we verified that cells entrain to temperature rhythms in vitro. Under constant temperature conditions, the LTCC antagonist verapamil shortened the circadian period, and the RYR antagonist dantrolene lengthened the period. However, neither drug affected temperature entrainment. Fibroblasts from BD patients and controls also entrained to temperature. In cells from BD patients, the rhythm amplitude was lower under entrained, but not constant, conditions. Temperature entrainment was otherwise similar between BD and control cells. However, the CACNA1C genotype among BD cells predicted the degree to which cells entrained. We conclude that assessment of rhythms under entrained conditions reveals additional rhythm abnormalities in BD that are not observable under constant temperature conditions.

KEYWORDS:

Bipolar disorder; Calcium channel; Circadian rhythm; Gene expression

PMID:
31192224
PMCID:
PMC6528084
[Available on 2020-04-01]
DOI:
10.1159/000497354

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