July 29, 2005
Molecule Provides a Missing Link in Understanding Depression
Researchers have discovered a regulatory molecule that links faulty
dopamine signaling in the brain to the neural machinery that breaks
down in people who suffer from depression.
The findings may explain why commonly prescribed antidepressants can
take weeks to work and why the drugs are ineffective for some people.
The researchers said their findings could open the way for the
development of antidepressant drugs with improved efficacy.
“This study pinpoints a specific pathway that implicates Par-4 in this process, which opens new possibilities for developing improved antidepressants.”
Li-Huei Tsai
The researchers, led by Howard Hughes Medical Institute investigator
Li-Huei Tsai at Harvard Medical School, published their findings in the
July 29, 2005, issue of the journal Cell.
According to Tsai, one of the longstanding puzzles in the treatment
of depression has been the long lag time that it takes before
antidepressants begin to work. These drugs ameliorate depression by
increasing levels of the neurotransmitters serotonin and/or
noradrenaline in the brain. Since the clinical effects of these drugs
are usually significantly delayed, it is now believed that their
efficacy depends on changes to later events in the signaling pathway
resulting from adaptation to chronic treatment, said Tsai.
Neurotransmitters such as serotonin and dopamine are molecular
“messengers” that neurons fire at protein receptors on the
surface of neighboring neurons. Drugs that influence the levels of
these neurotransmitters are central to treating a wide range of
neurological disorders.
In the current research, lead author Sang Ki Park sought to
understand the little-known signaling pathways in the cell that are
triggered by activation of the D2 receptor. He first conducted a broad
screen for proteins that interacted with a central regulatory segment
of the D2 receptor.
One of the proteins that the screen revealed, surprisingly, was a
regulatory molecule involved in the cell's suicide program, called
prostate apoptosis response 4 (Par-4) Apoptosis is the mechanism by
which the body rids itself of unneeded or damaged cells.
Further studies revealed that Par-4 was produced in the same neurons
where D2 receptors function, and that it competes with another key
signaling molecule, calmodulin, to bind to D2 receptors. The outcome of
this competition depends on calcium, one of the most important
regulators of neuronal function, said Tsai.
The researchers found that knocking out Par-4 in mouse neurons or
disrupting its interaction with the receptor caused a loss of the
normal inhibition of another key regulatory molecule, called cyclic
AMP.
The behavioral consequences of loss of Par-4 function were striking,
the researchers found. Mice deficient in Par-4 activity showed
depression-like behaviors in multiple tests. When placed in a
water-filled chamber, they gave up swimming as a means of escape more
quickly than do normal mice. When suspended by their tails, the mutant
mice try less to wriggle free and instead hung limply. When presented
with food in an open space, which mice perceive as an uncomfortable
setting, they showed less motivation to overcome their discomfort and
obtain the food, despite hunger. Furthermore, they showed reduced
motivation to explore open spaces than do normal mice, said Tsai. Other
tests confirmed that anxiety was not the basis of the abnormal
behaviors in the Par-4-deficient mice, she said.
Identifying Par-4's role in dopamine-mediated signaling could have
important scientific and clinical implications, said Tsai. “These
are very exciting results for two reasons,” she said.
“First, they indicate the importance of the signaling pathway
mediated by the D2 receptor in depressive behavior. While there had
been interesting studies on the involvement of dopamine D2 receptor in
depression, the mechanistic link at a molecular level has never been
clear.”
“Secondly, this study pinpoints a specific pathway that
implicates Par-4 in this process, which opens new possibilities for
developing improved antidepressants,” she said. Tsai said that
further studies in her laboratory would aim not only to understand the
Par-4 regulatory pathway in greater detail, but also to explore drugs
that could affect its normal function.
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Jim Keeley
