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Depressed Mice Reveal Critical Chemical Pathway for Treatment

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Duke Health News 919-660-1306

DURHAM, N.C. – Blocking production of a single enzyme
alleviates symptoms of depression and anxiety in mice that have
low serotonin levels, Duke University Medical Center
researchers have found.

Serotonin, a chemical that helps brain cells communicate
with one another, is the target of the most successful
anti-depressant medications. Low levels of serotonin are
implicated in depression and many other psychiatric disorders,
including increased anxiety, aggression and
obsessive-compulsive disorder.

The Duke team created mice with a mutation in the gene for
tryptophan hydroxylase 2 (Tph2), which helps make serotonin in
the brain. An equivalent human mutation has been identified in
some people with unipolar major depression. These patients
often show resistance to treatment with SSRI antidepressant
drugs.

Mice with the mutation had 80 percent less serotonin in
their brains than normal mice and exhibited behavioral changes
that mirror the symptoms of humans with low serotonin.

However, the study revealed a possible means for alleviating
these symptoms. The drop in serotonin levels was accompanied by
an increase in the activity of another enzyme, called glycogen
synthase kinase 3 (GSK-3), which helps a cell respond to
chemical signals, including serotonin.

Communication between cells operates much like a string of
medieval signaling towers – a fire lighted in one tower alerts
the next in the chain, quickly transmitting a message across
far distances. The Duke researchers discovered that blocking
one of these signaling towers, GSK-3, restored normal behavior
in the mutant mice.

The findings appear in the January 29, 2008 edition of the
Proceedings of the National Academy of Sciences. The study was
funded by the National Institutes of Health, the Lennon Family
Foundation, NARSAD and the Canadian Institutes of Health
Research.

GSK-3 is well known in the pharmaceutical industry – many
different psychiatric drugs block the enzyme, including
lithium, selective serotonin reuptake inhibitors (SSRIs),
tricyclic antidepressants and monoamine oxidase inhibitors
(MAOIs).

The researchers tested the SSRI drug fluoxetine (Prozac) in
the mutant mice, finding that short-term treatment relieved the
animal's depressive symptoms and inhibited GSK-3 activity in
the brain. The team is now evaluating the effects of long-term
treatment with SSRI drugs.

They also prevented depression from developing by breeding
mice with a mutation in the gene for GSK-3. "That GSK-3 is
involved was expected. But the fact that removing one version
of the GSK-3B gene reversed the behavior was quite surprising
to us," said lead author Jean-Martin Beaulieu, Ph.D., now at
Université Laval in Quebec. "This suggests that serotonin's
effects on mood and aggression may be partly controlled through
regulation of GSK-3 activity."

The dramatic drop in serotonin seen in the mice is caused by
a single-letter difference in the spelling of a gene that has
200,000 letters of DNA code. This one-letter change is called a
single nucleotide polymorphism, or SNP – a site where the DNA
sequence of individuals differs by just one of four nucleotides
(A, T, C or G). For example, some people may have G at a
particular site, while others have an A. The SNP studied by the
Duke researchers affects the Tph2 gene, built of some 100,000
nucleotide pairs.

The study also confirms that the Tph2 enzyme is critical for
making brain serotonin, said Xiaodong Zhang, Ph.D., study
co-author and an assistant professor at the Duke-NUS Graduate
Medical School Singapore. The results imply that humans with
this mutation may have serious deficits in brain serotonin, he
said.

In addition to revealing new clues to serotonin signaling in
the brain, the Tph2-mutant mice could also serve as an animal
model of drug-resistant depression. The Duke researchers have
patented the strain of mice used in the study, said senior
study author Marc Caron, Ph.D., James B. Duke professor of cell
biology.

"These animals may be one of the better models for
preclinical studies," Caron said. "We now have an animal model
that mimics many of the things you would expect of people that
are depressed."

Collaborators on the study include Ramona Rodriguiz, Tatyana
Sotnikova, Michael Cools, William Wetsel and Raul Gainetdinov,
all of Duke.

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