Deleting Gene in Brain Cells Mimics Effects of Antidepressants

Ralph DiLeone

Deleting a specific gene in particular cells in the brain has the same effect as antidepressants on mice conditioned to be depressed, according to researchers at The University of Texas Southwestern Medical Center at Dallas and Yale School of Medicine.

“The results have implications for a number of psychiatric conditions, including depression and post-traumatic stress disorder where stressful events can have significant and long-lasting consequences on social behavior and interactions,” said Ralph DiLeone, assistant professor in the Department of Psychiatry at Yale and a co-author of the report that appeared in the recent issue of the journal Science.

The researchers repeatedly exposed the subject mice to unfamiliar, aggressive mice. The normally social subjects were conditioned to be “defeated” and have a social aversion to mice they didn’t know. Giving the mice common antidepressants reversed this aversion.

Videotracking data from control and defeated mice in the absence and presence of a social target.

The researchers then showed that the function of a specific gene, brain-derived neurotrophic factor (BDNF), is critical to the development of social aversion in response to the repeated aggressive behavior. They demonstrated this by using viral technology developed by DiLeone to inactivate the gene specifically in cells of the ventral tegmental area of the brain. This region has a high concentration of dopamine neurons and is hypothesized to provide BDNF protein to the nucleus accumbens, a circuit that has been studied for its role in drug addiction and motivated behavior.

“Mice that were missing the gene,” said DiLeone, “did not develop the defeated behavior, suggesting that ventral tegmental area expression of the BDNF gene is critical for the development of the socially-withdrawn phenotype.”

The researchers also used detailed gene profiling to demonstrate that the removal of the BDNF gene opposes the effects of repeated social stress on gene expression in the nucleus accumbens.

DiLeone said the reversal of social aversion in mice, as with antidepressant treatment in humans, required long-term treatment, suggesting common mechanisms of molecular and neural plasticity.

Eric Nestler, M.D., chair of psychiatry at UT Southwestern, was senior author, and Olivier Berton, was lead author. Also from UT were Colleen McClung, Lisa Monteggia, David Self, Vaishnav Krishnan, William Renthal, Nadia Tsankova, Scott Russo, and Danielle Graham, and Carlos Bolanos of Florida State University and Maribel Rios of Tufts School of Medicine.

Science 311: 864-868 (February 10, 2006)

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