Serotonin is one of the main neurotransmitters in the central nervous system and until relatively recently it was thought that one enzyme - tryptophan hydroxylase (Tph1) - was responsible for making serotonin throughout the nervous system. Last year a second version of the enzyme, dubbed tryptophan hydroxylase-2, was discovered by researchers at Germany's Max Delbruck Centre for Molecular Medicine in Berlin-Buch.
Researchers subsequently showed that Tph1 was responsible for making serotonin in peripheral nerves, while Tph2 was the predominant form found in the brain. In the latest study, scientists from Duke University Medical Centre in North Carolina have revealed that Tph2 itself exists in two forms.
The Duke team screened the brains of several mouse strains for the Tph2 gene. To their surprise, they found not one version of the gene, but two, which differed from each other in a single nucleotide.
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, they reported. A mouse strain with one variant produced 50 to 70 per cent 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," they said.
Exploiting these findings might provide a useful approach to developing animal models of serotonin-related disorders, as well as for understanding psychiatric disorders and their treatment, the researchers said.
"For the first time, we've identified a naturally occurring genetic difference that controls the production of serotonin in the brain," said Marc Caron, professor of cell biology at Duke and the senior author in 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 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 (GlaxoSmithKline's Seroxat/Paxil), sertraline (Pfizer's Zoloft) and fluoxetine (Eli Lilly's 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 Duke team now 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.