Repeated defeat by dominant animals causes a depression-like syndrome in mice that is accompanied at the molecular level by changes in gene expression in the hippocampus, according to an article published online February 26th by Nature Neuroscience.

Researchers found that silencer molecules had halted gene expression for a key protein in the hippocampus in mice that had developed the social-withdrawal behaviors. By activating a compensatory mechanism, an antidepressant temporarily restored animals’ sociability and protein expression, the silencer molecules blocked gene expression after the antidepressant was discontinued.

A true cure for depression would likely have to target this persistent stress-induced scar, said the researchers, led by Eric Nestler, MD, of The University of Texas Southwestern Medical Center.

In the study, mice exposed to aggression by a different dominant mouse daily for 10 days became socially defeated; they vigorously avoided other mice, even weeks later. Expression of a representative gene in the hippocampus decreased three-fold and remained suppressed for weeks. However, chronic treatment with imipramine restored expression of the gene for brain derived neurotrophic factor (BDNF) to normal levels and reversed the social withdrawal behavior. BDNF in the hippocampus has been linked to memory, learning and depression, but Nestler said social defeat stress probably similarly affects other genes there as well.

The researchers pinpointed how social defeat changes the BDNF gene’s internal machinery. They traced the gene expression changes to long-lasting modifications in histones, proteins that regulate the turning on-and-off of genes via a process called methylation. Methyl groups, the silencer molecules, attach themselves to the histones, turning off the gene. Notably, imipramine was unable to remove these silencer molecules, suggesting that they remained a latent source of vulnerability to future depression-like responses to stress.

Imipramine reversed the suppressed BDNF gene expression by triggering a compensatory mechanism, acetylation, in which molecular activators attach themselves to the gene and overcome the silencer molecules. Imipramine turned off an enzyme (Hdac5) that degrades the activators, allowing them to accumulate.
“The molecular scar induced by chronic stress in the hippocampus, and perhaps elsewhere in the brain, can’t be easily reversed,” said Nestler. “To really cure depression, we probably need to find new treatments that can remove the silencer molecules.”