New research reveals a protein involved in lifting depression

Paul Greengard, Ph.D.,a Nobel Laureate researcher says that mice deficient in a protein, called p11, display depression-like behaviours, while those with sufficient amounts behave as if they have been treated with antidepressants.

Greengard, a Rockefeller University neuroscientist who received the 2000 Nobel Prize in Physiology or Medicine for discoveries about the workings of such neuronal signaling systems, has found that p11 appears to help regulate signaling of the brain messenger chemical serotonin.

Serotonin is a key target of antidepressants, which has been implicated in psychiatric illnesses such as depression and anxiety disorders.

NIH director Elias Zerhouni, M.D. says the newfound protein may provide a more specific target for new treatments for depression, anxiety disorders and other psychiatric conditions.

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 also suggested that serotonin receptors are essential in regulating moods and in mediating the effects of SSRIs, but the complex serotonin system, and exactly how these receptors work remains a mystery.

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 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.

In order to test this theory, the researchers examined p11 levels in the brains of depressed humans and “helpless” mice, considered a model of depression since they exhibit behaviours similar to those of depressed humans.

They compared these two groups to non-depressed humans and control mice and found the levels of p11were found to be substantially lower in depressed humans and helpless mice, suggesting 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 therapy (ECT).

Greengard says the three different methods of treating depression all caused an increase in the amount of p11 in the brains of the mice, and is convincing evidence that p11 is associated with the main therapeutic action of antidepressant drugs.

Since both humans and mice with the symptoms of depression were found to have significantly lower levels of p11 in brain cells compared to non-depressed animals, Greengard and colleagues hypothesize that if p11 levels are increased, mice would exhibit antidepressant-like behaviours, and if p11 were reduced, mice would exhibit depression-like symptoms.

Greengard says it seems that antidepressant medications need to increase p11 levels in order to be effective, and he hopes future studies will clarify exactly how antidepressants increase levels of this molecule.

They report on their findings in the January 6, 2005 issue of Science.