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p11 gene may play a key role in determining susceptibility to depression

A research by an international team of scientists, led by Rockefeller University researchers in Paul Greengard's laboratory of Molecular and Cellular Neuroscience, has shown that a gene called p11 is closely related to serotonin transmission in the brain, and may play a key role in determining a person's susceptibility to depression.

The findings are published in the journal Science.

" We have shown that a gene called p11 is involved in the multiple complex changes that underlie depression," says Per Svenningsson, first-author on the paper. " Our findings demonstrate that patients with depression, and mice that model this disease, have decreased levels of p11 protein, and they suggest that drugs that increase p11 are likely to have anti-depressant properties."

Serotonin binds to 14 different receptors on a cell's surface. One receptor in particular, known as 1B, plays a crucial role in regulating serotonin transmission in the brain. Recent studies have suggested a role for the serotonin 1B receptor in depression, as well as in obsessive-compulsive disorder, drug addiction, anxiety, aggression and sleep.

Intrigued by these studies, Svenningsson and colleagues used a blind screen called a yeast two-hybrid screen to identify proteins that associate with the serotonin 1B receptor.
They found an association with a protein called p11, a protein previously identified as a regulator of the localization of several proteins on the cell's surface.

The researchers analyzed tissue from a mouse model of depression as well as post-mortem tissue from depressed human patients, and found decreased levels of p11 protein in both cases.
On the other hand, p11 levels increased in rats and mice that were treated with anti-depressant medications or electroconvulsive therapy.

To further test the connection, Svenningsson and his colleagues genetically engineered two strains of mice: one that produced more p11 than normal and another that produced no p11 at all.
They found that mice that overexpress p11 were hyperactive and, in a test designed to identify depression in rodents, acted just like mice that were on anti-depressant medication.
Mice that lacked p11, meanwhile, acted depressed and showed less responsivity to anti-depressant medications.

Taken together, the findings point to p11 as a new target for developing depression treatments.

" In addition to exploring ways to increase p11 in depressed patients, it may also be possible to develop peptide-based compounds that can mimic the action of p11 to achieve a new class of anti-depressant compounds," Svenningsson says.

Source: Rockefeller University, 2006