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CLOCK Gene and Bipolar Disorder

An Important Role for Cholecystokinin, a CLOCK Target Gene, in the Development and Treatment of Manic-like Behaviors

Arey RN, Enwright JF III, Spencer SM, Falcon E, Ozburn AR, Ghose S, Tamminga C, McClung CA.

Bipolar disorder, characterized by alternating periods of mania and depression, has been associated with disruptions in circadian rhythms, the biological processes that occur on a roughly 24-hour cycle. Evidence suggests that the mood cycles of the illness result from disruptions of the brain’s molecular clockwork that controls circadian rhythms through gene expression. In a recent study led by Dr. Colleen McClung, Associate Professor of Psychiatry, researchers modeled human mania using mice with a mutation in a key component of the clockwork, a gene aptly named CLOCK. This study sheds light on possible mechanisms underlying CLOCK’s involvement in bipolar disorder, finding that levels of the neuropeptide cholecystokinin (CCK) were reduced in the ventral tegmental area (VTA) of CLOCK mutant mice. In addition, the study showed that knockdown of CCK in wild type animals produced a manic-like phenotype that was reversed with chronic lithium treatment. The increase in CCK was required for lithium’s therapeutic effect, suggesting that CCK may play a role in lithium’s mechanism of action. Corroborating their mouse data, the researchers also observed an increase in CCK expression levels in postmortem VTA tissue from bipolar disorder subjects who were treated with mood stabilizers.

Contributors:
John F. Enwright III, Angela R. Ozburn, Colleen A. McClung (University of Pittsburgh School of Medicine, Department of Psychiatry and Translational Neuroscience Program, Pittsburgh, PA)
Arey RN, Spencer SM, Falcon E, Ghose S, Tamminga C (University of Texas Southwestern Medical Center, Department of Psychiatry, Dallas, TX)

The results of this investigation were published in  Molecular Psychiatry. Click here for a link to the abstract