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.