November 13, 2013
By Michael Craig Miller M.D.
Harvard Medical School
Mice may be teaching us about the genetic basis of bipolar disorder. This mood disorder, which is often called by its older name, manic-depressive illness, is characterized by wide mood swings that range from high (manic) to low (depressed).
Scientists, who published their research in 2007 in the Proceedings of the National Academy of Science (PNAS), studied mice that have a variation or mutation in a gene called the Clock gene. The Clock gene helps regulate the body's daily circadian rhythm — the ups and downs of biological functions that occur over a 24-hour period.
Mice with this variant gene show signs similar to human mania. When the scientists gave these mice lithium, the oldest drug treatment for mania, they became more like typical mice.
Researchers have hoped this animal model of mania may help scientists develop better treatments for people with bipolar disorder. Here's a closer look at the possible role of this gene in bipolar disorder.
Biological Clocks and Genes
An internal clock system is so basic to life that it's found throughout nature. It's remarkable — the human version is quite similar to the ones found in mice, fruit flies and even bread mold.
Scientists have known about these internal biological clocks for almost 200 years. Only recently have they begun to understand how genes control those clocks through a feedback system or loop.
When a gene is turned on or "expressed," it begins to produce specific proteins. As protein concentrations in the organism increase, the genes recognize this and turn off. Protein levels then drop again, signaling the gene to turn back on and restart production. This cycle takes about 24 hours in humans.
Mammals have a biological clock in the brain that consists of a pair of small nerve-cell clusters called the suprachiasmatic nuclei (SCN). Each cell in the SCN is a tiny clock. The cells stay in synch by sending chemical signals to one another. But they also need to know what's going on out in the world. So specialized cells in the eyes detect the intensity of light and that information is sent to the SCN over a nerve circuit. Thus, the SCN keeps in step with the light-dark cycle brought on by the earth's rotation. The SCN also sends signals to key areas of the brain that control daily body rhythms, such as variations in temperature and hormone production.
The Clock Gene and Bipolar Disorder
One variety of human clock gene is seen more often in people who have symptoms of bipolar disorder. These individuals are more likely to have manic episodes. Even when not manic, they sleep less and wake earlier than average. Similar fluctuations have been observed in the mutant mice.
There's ample evidence that bipolar disorder is associated with an irregular circadian cycle. The symptoms of mania involve disturbances of the daily patterns of sleeping and waking, energy, appetite and hormone production. In some people with bipolar disorder, moods change with the seasons. The shorter days of winter bring depression. Long summer days trigger mania. Clinicians often tell bipolar patients to get enough sleep and stay on a regular schedule to reduce the risk of a manic or depressive episode.
Correcting Faulty Genes
The researchers involved in the PNAS study found that mice with the Clock gene variant were more active and more likely to seek out rewards or try out new situations than mice with the more common or "wild-type" Clock gene. The mice with the variant gene also had stronger responses to pleasurable stimuli than the wild-type mice and showed fewer signs of the behavior that looks like depression and anxiety. They were more likely to take risks or be impulsive, too.
Researchers were able to change the mouse behavior in two ways. They gave the mice a low dose of lithium and noticed that they behaved more like the "wild-type" (or common) mice. And they also went right to the source of the problem — using a virus, they inserted a properly functioning protein into a gene in the brain's reward center. This canceled out the effect of the mutation. Following the procedure, the mice showed levels of activity and anxiety-like behavior that were more like "wild-type" mice.
Applying This to Humans
Unfortunately, we are nowhere near being able to correct genetic variations to cure human bipolar disorder. The mice in this mutant strain don't appear to get depressed, so they can only teach us about mania. And, in any case, it is highly unlikely that bipolar disorder in humans is the result of a variation in just one gene.
But this research is very promising, because it demonstrates in principle how future treatments might work. The study also shows how important it is to study the connection between circadian rhythms, the brain's reward system and mood disorders. What we learn from these mice increases the chance that scientists will find ways to correct a major cause of human distress.
Michael Craig Miller, M.D. is the former editor-in-chief of the Harvard Mental Health Letter and an assistant professor of psychiatry at Harvard Medical School. Dr. Miller has an active clinical practice and has been on staff at Beth Israel Deaconess Medical Center for more than 30 years.