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DURHAM, N.C. -- 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.