Some of you, like me, suffer from bipolar disorder or might know someone who does, so I thought I’d take this opportunity to write a little about the creation of a mouse model to study the genetics that are thought to underlie the manic phase of bipolar disorder — a phase that has not been well understood so far.

Bipolar disorder, or manic-depressive illness, is a psychiatric condition that affects a person’s moods. Typically, a person who suffers from a classical bipolar disorder (Also known as bipolar affective disorder, type 1) will have periods of depression that alternate with mania or hypomania. Mania and hypomania are characterized by elation, irritability, reduced need for sleep and increased goal-directed behaviors. These characteristic mood swings can be associated with the season; depression being more common in winter with either mania or hypomania typically occurring in summer or at the change of the seasons.

Bipolar disorder in its various forms affects slightly less than 3 percent of the population. It is associated with an increased risk of suicide, substance abuse, and vocational disability. Unfortunately, there are no animal models for bipolar disorder, so it has not been possible to carefully study the genetics of the disorder (there are mice who exhibit depression and thereby act as molecular models for that illness). A paper that was recently sent to me by a reader examines the underlying genetics of bipolar disorder and uses that information to create a mouse model of the manic phase of bipolar disorder so scientists and psychiatrists can study this aspect of the condition.

Because of its cyclical nature, bipolar disorder has been thought to be tied to the circadian rhythm. In the suprachiasmatic nucleus of the brain, there are several gene products that dictate one’s circadian rhythm; CLOCK and BMAL1, Period (Per) and Cryptochrome (Cry), and a host of other proteins (see figure 1, above). But which gene(s) are essential to mania?

Recent studies of glycogen synthase kinase-3 beta (GSK3beta) have identified this enzyme as the central regulator of the circadian clock and further, GSK3beta is a known target of the mood-stabilizing drug, lithium [Gould & Manji (2005) Neuropsychopharmacology 30:1223-1237] that is commonly used to treat bipolar disorder. Lithium is known to increase the length of the circadian period in fruit flies, Drosophila, and in rodents. Additionally, valproate (depakote) acts on on the circadian cycle by altering the expression of several circadian genes in the amygdala [Ogden et al., (2004) Mol Psychiatry 9:1007-1029] and treatment with fluoxetine (prozac) has been shown to target this pathway by increasing the expression of Clock and Bmal1 genes in the hippocampus [Manev & Uz (2006) Trends Pharmacol Sci 27:186-189]. So it appears that either, or both, CLOCK and its binding partner, BMAL1, play a central role in triggering the manic phase of bipolar disorder.

Furthermore, studies in humans reveal that variants, or polymorphisms, in Clock and its binding partner, Bmal1, are suspected to play a role in the frequency and severity of the manic phase of bipolar disorder. Thus, if one of these genes can be altered in mice, it will likely be possible to construct a mouse model in which to study the manic phase of bipolar disorder.

Using this information, a research team headed by Kole Roybal, mutated the Clock gene in mice and then subjected them to a series of behavioral experiments to determine the nature of this mutation in a living animal. These behavioral experiments on the mice expressing the mutated CLOCK protein showed that they exhibited locomoter hyperactivity, disrupted circadian rhythms, decreased sleep, reduced anxiety levels, less helplessness, and an increased preference for cocaine — similar to bipolar humans exhibiting mania. They also found that the experimental mice responded to treatment by lithium similarly to many humans with bipolar disorder.

Unfortunately, these CLOCK-mutated mice do not cycle between mania and depression, as bipolar humans do, so they are only useful for better understanding the underlying molecular aspects of mania/hypomania. Because they behave similarly to manic bipolar humans, and because they respond to lithium similarly to bipolar humans, these mice represent a good and useful beginning for understanding how to successfully manage bipolar disorder in humans.

Sources

Mania-like behavior induced by disruption of CLOCK by Kole Roybal, David Theobold, Ami Graham, Jennifer A. DiNieri, Scott J. Russo, Vaishnav Krishnan, Sumana Chakravarty, Joseph Peevey, Nathan Oehrlein, Shari Birnbaum, Martha H. Vitaterna, Paul Orsulak, Joseph S. Takahashi, Eric J. Nestler, William A. Carlezon, Jr., and Colleen A. McClung. Proceedings of the National Academy of Sciences (Mar 22, 2007) doi:10.1073/pnas.060962510407.

What can a clock mutation in mice tell us about bipolar disorder? by Joseph T. Coyle. Proceedings of the National Academy of Sciences (Apr 2, 2007) doi:10.1073/pnas.0701491104. (IMAGE)