Thursday, April 19, 2007

Bipolar disorder - related to a disorder in the Clock gene?

Coyle offers a review in the April 10 issues of PNAS of a paper by Roybal et al. showing that mutation of the clock gene in mice causes them to show symptoms of bipolar behavior. I give you Coyle's summary:
Bipolar disorder, also known as manic-depressive illness, is characterized by episodes of mania and episodes of depression usually interspersed with periods of relatively normal mood. During the manic phase, affected individuals exhibit elevated mood, irritability, increased activity, reduced sleep, hypersexuality, and increased goal-directed activities. Bipolar disorder in its various forms affects >3% of the population and is associated with a high risk for suicide, substance abuse, and vocational disability. Although several animal models for major depressive disorder have been developed, there are no plausible models for bipolar disorder. In this issue of PNAS, Roybal et al. describe the results of a systematic analysis of the behavior of a mouse with a deletion of exon 19 in the Clock gene, which shows remarkable parallels to the symptoms observed in individuals in an episode of mania. The Clock mutant mice exhibit hyperactivity, decreased sleep, reduced anxiety, and increased response to cocaine, sucrose, and medial forebrain bundle stimulation. Furthermore, many of these behaviors can be reversed by transfection of the ventral tegmental area (VTA) dopaminergic neurons with WT Clock gene or by treatment with therapeutic doses of lithium (Li+), a commonly prescribed mood stabilizer.

And the abstract of the article:
Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood.

1 comment:

  1. That's why you don't want to mess with me before I've had my caffeine in the morning (not to mention after I've had too much). I bet the idea for the experiment occurred to somebody over breakfast.