McLean Researchers Identify Genes that Trigger Depression

Could be key to more effective treatments

September 26, 2001 -- Belmont, MA -- Activation of genes within key brain regions can trigger symptoms of depression in rats, scientists at McLean Hospital have discovered. Led by William Carlezon, PhD, director of McLean's Behavioral Genetics Laboratory, a multi-disciplinary group of researchers has focused on a link between a factor that controls gene expression in the brain, called CREB, and mood disorders.

In a paper published in the September issue of The Journal of Neuroscience, Carlezon and his colleagues describe the development of methods that allowed them to selectively activate or deactivate CREB. They found that activation of CREB in frontal portions of the brain caused signs of depression that normally occur only in response to stressful situations.

"Stress causes many changes in the brain," said Carlezon. "We have identified CREB as a critical element in a chemical pathway that, when activated, can cause certain symptoms of depression."

Carlezon's group also found that blocking CREB lessened the effects of stress, and made rats behave as if they were being treated with antidepressant drugs. By comparing differences in the genetic profiles of rats with activated or deactivated CREB, they uncovered evidence that the gene for one of the body's own pain-killing molecules, dynorphin, serves as a "switch" for some signs of depression. The identification of this "switch" could lead to new strategies for treating depression.

"Once activated, CREB controls some of the genes that encode opiate-like peptides in the brain. Some of these peptides cause things like a 'runner's high,' but others make us feel sick or uncomfortable. We have found evidence that, in the case of depression symptoms, the relevant effect of CREB is to activate a peptide called dynorphin," said Carlezon.

The group reports that, in preliminary tests, chemical blockers of brain receptors for dynorphin appear to have strong antidepressant effects in animal models. Carlezon believes that these studies provide important clues about new types of chemicals that could be used to treat depression, although he emphasized that this is a very early development in the search for more effective treatments.

"Dynorphin blockers are very difficult to make, and they are not yet ideal," Carlezon said, "However, the value of this kind of work is that it gives us new ideas about innovative approaches to the study and treatment of depression, and the development of future generations of antidepressant drugs."
Carlezon's colleagues involved in this study include Christine Konradi, PhD, director of McLean's Neuroplasticity Laboratory and Rachel Neve, PhD, director of McLean's Molecular Neurogenetics Laboratory.