September 29, 2008

MONDAY, Sept. 29 ( — People who are missing a snippet of DNA from a brain-receptor gene are less likely to develop bipolar disorder than those with a longer version of the same gene.

The shorter version of the gene, which is called GRIK4, makes a more stable receptor for glutamate, a key brain-signaling molecule.

“This means it is part of the machinery that helps brain cells talk to each other,” says study author Benjamin Pickard, PhD, a geneticist at the University of Edinburgh in Scotland.

About 1% of people around the world have bipolar disorder, also known as manic depression, a psychiatric condition characterized by cycling episodes of depression and mania.

Pickard and his colleagues originally identified the GRIK4 gene in 2006 when they were studying a patient with schizophrenia and mental retardation. More testing suggested the gene might play a role in bipolar disorder as well as schizophrenia, according to the report in Proceedings of the National Academy of Sciences.

In the new study, they tested 356 people with bipolar disorder and 286 healthy people, and found healthy people were more likely to have the short version of GRIK4 than those with bipolar.

However, just because you have a short version of the gene doesn’t mean you won’t get the disease—it just decreases your risk.

For example, about 40% of healthy people have the shorter version, but only 20%–30% of those with bipolar disorder have the short version, Pickard says.

“Obviously this is not the only gene that leads to or protects against bipolar disorder,” says Colleen A. McClung, PhD, an assistant professor of psychiatry at the University of Texas Southwestern Medical Center in Dallas. However, the discovery of this gene variant does bolster the idea that glutamate activity is important in the development of this disease, she explains.

Next: Why it's a bad idea to get a test for this gene

Why it's a bad idea to get a test for this gene
One theory is that that too little glutamate signaling in the brain can cause bipolar disorder.

If that is true, it would seem logical that using medication to increase glutamate activity in the brain would be helpful. However, too much glutamate signaling can cause seizures and epilepsy, says Pickard.

“So altering glutamate would have to be a careful balancing act if this is to be a potential target for the design of new drugs,” he says. “There are currently no bipolar-disorder drugs based on this biochemistry—most, like lithium, act as mood stabilizers.”

It’s not a surprise that glutamate may play a role in bipolar disorder, says Gary Sachs, MD, director of the bipolar clinic and research program at Massachusetts General Hospital in Boston.

“In simplest terms, you can imagine in the brain there’s something that's the equivalent of an accelerator and there’s something that's the equivalent of brakes,” says Dr. Sachs. Glutamate is the equivalent of the accelerator, and the GABA system, another signaling molecule, is the equivalent of the brakes, he explains.

When patients start to develop symptoms, it could be because “all the cars are piling up because they don’t have brakes. But it might look the same because all the cars are piling up because the accelerator is jammed,” he says.

These “traffic jams” can produce extra excitation in the brain that can cause people to be very depressed or very excited. “The usually tightly regulated neuro-circuitry gets out of control,” Dr. Sachs says.

However, he adds that dozens of as-yet-undiscovered genes may play a role in these traffic jams.

“We really, really don’t want to encourage people to go to the shysters offering these [genetic] tests,” he says. “I think that is a very undesirable outcome.”

Ten years from now, people might be able to get a panel of tests for bipolar-risk genes, but not now, according to Dr. Sachs.

“This is one piece of information in a big jigsaw puzzle," he says. "Right now we’re really happy to have this piece, but this is a 30,000-piece puzzle—and this is piece number 4 or 5."

By Theresa Tamkins