Identification of a naturally occurring genetic difference that controls the production of serotonin in the brain

Researchers at Duke University Medical Center have provided the first direct evidence in mice for the role of an enzyme that specifically controls the production of serotonin in the brain.

Different versions of that serotonin enzyme have a major effect on brain levels of the chemical messenger, which has been linked to many basic behavioral and physiological functions including mood, emotion, sleep and appetite, the researchers reported in the July 9, 2004, issue of Science. The finding has major implications for understanding psychiatric disorders and their treatment, the researchers said.

Serotonin is a "neurotransmitter," a chemical that one neuron uses to trigger a nerve impulse in its neighbors. Thus, serotonin levels can profoundly affect brain function, and therefore behavior.

"For the first time, we've identified a naturally occurring genetic difference that controls the production of serotonin in the brain," said Howard Hughes Medical Institute investigator Marc Caron, Ph.D., James B. Duke professor of cell biology at Duke and senior author of the study.

The finding in mice sets the stage for new insights into the role the serotonin enzyme and the gene that encodes it might play in animal behavior and human psychiatric disorders, said the researchers. Low levels of serotonin have been implicated in many disorders such as depression, anxiety, post-traumatic stress disorder and attention deficit hyperactivity disorder.

The enzyme might also influence patients' responses to the class of drugs known as selective serotonin re-uptake inhibitors or SSRIs, they added. SSRIs include paroxetine (trade name Paxil), sertraline (trade name Zoloft) and fluoxetine (trade name Prozac). The influence of the serotonin enzyme raises the possibility that a genetic test to distinguish which version of the gene a patient has could predict the patient's response to the drugs, Caron said.

The brain is a network of billions of cells called neurons. When stimulated, neurons fire, sending a wave of electrical charge from one end to the other. To bridge the gap between nerves, the neurons release chemical neurotransmitters, including serotonin, that set off an impulse in receiving neurons. Once the original cell has passed its message on, it sops up the chemical it released to damp that signal and prepare for the next.

If serotonin levels are decreased, as may occur in patients with depression and other psychiatric disorders, communication among neurons stalls. SSRIs counteract the breakdown by slowing the re-uptake of serotonin, allowing the body to make the best use of abnormally low levels of the chemical messenger, the researchers explained.

Scientists had long considered the enzyme known as tryptophan hydroxylase (Tph1) to be the sole enzyme governing serotonin synthesis in the nervous system, Caron said. Last year, however, researchers at another institution found that a second enzyme, tryptophan hydroxylase-2 (Tph2), is present in the brain, while the earlier discovered Tph1 is found primarily in peripheral nerves.

The Duke team screened the brains of several mouse strains for the Tph2 gene. To their surprise, said Xiaodong Zhang, Ph.D., lead author of the study, they found not one version of the gene, but two.

The two gene variants differed in a single DNA unit, called a nucleotide. That difference altered the gene so that it produced a variant of the enzyme with a different amino acid unit and raised the possibility that the change might alter the protein function and production of serotonin, Zhang said.

Studying the effects of the enzyme variants in cultured cells, the researchers found that they had a major effect on the amount of serotonin the cells produced, the team found. That difference was also evident in the mice, the researchers reported. A mouse strain with one variant produced 50 to 70 percent less serotonin in their brains than did mice with the other variant.

"This single genetic difference has a huge impact on serotonin levels, confirming that the gene is fundamental in the synthesis of brain serotonin," said Zhang.

The findings will have an immediate practical impact, the researchers added. "Mouse strains that are the subject of much biomedical research have been known to have behavioral differences related to serotonin levels," Zhang said. "Now we've identified a major gene responsible."

Exploiting these findings might provide a useful approach to developing animal models of serotonin-related disorders, added Martin Beaulieu, Ph.D., a co-author on the study.

The team plans to look for similar genetic differences and their influence on brain chemistry in humans with psychiatric disorders. In contrast to the inbred mouse strains, Caron suspects that humans likely bear many versions of the serotonin gene.

Collaborators on the research include Tatyana Sotnikova, Ph.D., and Raul Gainetdinov, M.D.