Mutant 'Clock' Gene Implicated in Bipolar Illness

Disruption of the “Clock” gene, which regulates the biological clocks in mice, appears to be associated with the onset of mania-like behavior as the mice begin exhibiting behaviors similar to humans with bipolar disorder, University of Texas/Southwestern Medical Center researchers have found.

The new research, which appears in the online version of the Proceedings of the National Academy of Sciences, was supported by grants from the National Institute on Drug Abuse and National Institute of Mental Health.

“Clock” stands for “circadian locomotor output cycles kaput.”

“There's evidence suggesting that circadian genes may be involved in bipolar disorder,” Colleen McClung, M.D., an assistant professor of psychiatry and the study's senior author, told reporters at a media briefing.“ What we've done is taken earlier findings a step further by engineering a mutant mouse model displaying an overall profile that is strikingly similar to human mania. This will give us the opportunity to study why people develop mania or bipolar disorder and how they can be treated.”

McClung and her colleagues developed a strain of mice with a mutant Clock gene. Clock is thought to produce a protein that plays an integral role in the regulation of a complex feedback loop that modulates the body's circadian rhythms. The mutation results in a defective protein, interrupting the regulation of the feedback loop.

Mice with the Clock mutation show extreme levels of hyperactivity, reduced need for sleep, and heightened responses to novel stimuli, over the entire dark/light cycle of circadian rhythm. In addition, these mice show enhanced behavioral responses to psychostimulants such as cocaine and amphetamines.

McClung and her team put the mutant mice through a series of tests, observing the mice as they displayed an increase in goal-directed behaviors. Clock-mutant mice were much more likely to exhibit reward-seeking behavior, such as a significantly higher frequency of self-administration of an electrical stimulus to specific brain-reward circuits, applied through implanted electrodes.

In the mutant mice the researchers also observed hyperactivity, decreased sleep, decreased levels of anxiety-like symptoms, a greater willingness to engage in “risky” activities, lower levels of depression-like behavior, and increased sensitivity to the rewarding effects of substances such as cocaine and sugar.

“These behaviors correlate with the sense of euphoria and mania that bipolar patients experience,” McClung explained. “In addition, there is a very high comorbidity between drug usage and bipolar disorder, especially when patients are in the manic state.”

When the mice were given lithium, the majority reverted to normal behavioral patterns. After chronic lithium administration, the mice exhibited normal levels of anxiety- and depression-like behaviors in open-field, elevated-maze, and forced-swim tests.

The researchers also injected a functional Clock-gene protein into the medial forebrain bundle, a region known to control reward functions, and again observed a return to normal behaviors in the mice.

“While the Clock gene is expressed throughout the brain, it's really only been studied in one particular brain region, which is the one that's involved in circadian rhythms,” said McClung. “This is one of the first studies to show that Clock has a major effect on behavior in a different brain region—specifically the one that controls reward responses and mood.”

Eric Nestler, M.D., chair of the University of Texas/Southwestern's Department of Psychiatry and a study coauthor, said in a press release that the research is important because it establishes the first complete mouse model for studying bipolar disorder.

“The lack of an animal model for bipolar disorder has been a crucial limitation in our efforts to better understand the biological basis of the disorder,” Nestler said. “Dr. McClung's findings are therefore very important for the field and provide fundamentally new directions for one day developing improved treatments.”

An abstract of “Mania-Like Behavior Induced by Disruption of Clock,” is posted at<www.pnas.org/cgi/content/abstract/0609625104v1>.▪