|Nobelist Discovers Antidepressant Protein in Mouse Brain
A protein that seems to be pivotal in lifting depression has been discovered
by a Nobel Laureate researcher funded by the National Institutes of Health’s
National Institute of Mental Health (NIMH).
“Mice deficient in this protein, called p11, display depression-like behaviors,
while those with sufficient amounts behave as if they have been treated with
antidepressants,” explained Paul Greengard, Ph.D., a Rockefeller University neuroscientist
who received the 2000 Nobel Prize in Physiology or Medicine for discoveries about
the workings of such neuronal signaling systems. He and his colleagues found
that p11 appears to help regulate signaling of the brain messenger chemical serotonin,
a key target of antidepressants, which has been implicated in psychiatric illnesses
such as depression and anxiety disorders. They report on their findings in the
January 6, 2005 issue of Science.
“This newfound protein may provide a more specific target for new treatments
for depression, anxiety disorders and other psychiatric conditions thought to
involve malfunctions in the serotonin system,” said NIH director Elias Zerhouni,
Brain cells communicate with each other by secreting messengers, such as serotonin,
which bind to receptors located on the surface of receiving cells. Serotonin
selective reuptake inhibitors (SSRIs), medications commonly prescribed for anxiety
and depression, compensate for reduction in serotonin signaling by boosting levels
and binding of serotonin to receptors. Previous studies have suggested that serotonin
receptors are essential in regulating moods and in mediating the effects of SSRIs,
but given the complexity of the serotonin system, exactly how these receptors
work remains a mystery.
To explore how a particular serotonin receptor (5-HT1B) functions, Greengard
and colleagues conducted tests to find out what proteins these receptors interact
with in brain cells. They found that 5-HT1B interacts with p11, and according
to Greengard, p11 plays a role in the recruitment of receptors to the cell surface
where they are more functional.
This finding led the researchers to suspect that p11 levels might be directly
involved in the development of depression, anxiety and similar psychiatric illnesses
thought to involve faulty serotonin receptors. To test this idea, the researchers
examined p11 levels in the brains of depressed humans and “helpless” mice, considered
a model of depression since they exhibit behaviors similar to those of depressed
humans. They compared these two groups to non-depressed humans and control mice.
Levels of p11were found to be substantially lower in depressed humans and helpless
mice, which suggests that altered p11 levels may be involved in the development
of depression-like symptoms.
The researchers also examined the effect of treatments designed to boost weak
serotonin systems on p11 levels in brain cells by administering to mice two types
of antidepressants — a tricyclic, a monoamine oxidase (MAO) inhibitor — and electroconvulsive
“These three different ways of treating depression all caused an increase in
the amount of p11 in the brains of these mice,” said Greengard. “They all work
in totally different ways, but in all cases they caused the same biochemical
change. So, it’s pretty convincing that p11 is associated with the main therapeutic
action of antidepressant drugs.”
Since humans and mice with symptoms of depression were found to have substantially
lower levels of p11 in brain cells compared to non-depressed animals, Greengard
and colleagues hypothesized that if p11 levels were increased, mice would exhibit
antidepressant-like behaviors, and if p11 were reduced, mice would exhibit depression-like
As hypothesized, mice with over-expressed p11 genes, compared to control mice,
had increased mobility in a test that is used to measure antidepressant-like
activity. They also had more 5-HT1B receptors at the cell surface that were capable
of increased serotonin transmission.
The opposite occurred when researchers molecularly knocked out the p11 gene
in mice. Compared to control mice, knockout mice had fewer receptors at the cell
surface, reduced serotonin signaling, decreased responsiveness to sweet reward,
and were less mobile, behaviors which are considered depression-like. Also, the
5-HT1B receptors of p11 knockout mice were less responsive to serotonin and antidepressant
drugs compared to those of control mice, which further implicates p11 in the
main action of antidepressant medications.
“Manipulations that are antidepressant in their activity increased the level
of the protein and those which are depressant reduce it,” said Greengard. “It
seems as though antidepressant medications need to increase p11 levels in order
to achieve their effect.” Future studies should elucidate exactly how antidepressants
increase levels of this molecule, he added.
Also participating in the study: Per Svenningsson, Ilan Rachleff, Marc Flajolet,
The Rockefeller University; Karima Chergui, Xiaoqun Zhang, Karolinska Institute;
Malika El Yacoubi, Jean-Marie Vaugeois, Faculty of Medicine and Pharmacy, Rouen
Cedex, France; George G. Nomikos, Eli Lilly and Company.
NIMH is part of the National Institutes of Health (NIH), the Federal Government's
primary agency for biomedical and behavioral research. NIH is a component of
the U.S. Department of Health and Human Services.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.