Gene therapy cures depressed mice

Feb 13 2006

Researchers in the U.S. say that deleting a specific gene in the brain of mice that have been conditioned to be depressed, has the same effect as antidepressants.

Dr. Eric Nestler, chairman of psychiatry at the University of Texas Southwestern Medical Center and the study's senior author, says that disabling a memory molecule in the brain lifts depression in mice as effectively as using antidepressants.

It seems the depressed mice became more sociable when researchers deleted a memory molecule from their brains; scientists say they believe the finding might help treat human conditions such as social phobia and post-traumatic stress.

According to Dr Olivier Berton the report's lead author, they targeted a molecule in a section of the brain known to be related to sensations of pleasure and danger, often called the reward pathway, which has been studied in relation to drugs that are abused.

Deleting the molecule from this part of the brain meant that the mice were never depressed and fearful, Berton says, even though conditions were set up that normally would make them run and hide.

Mice are normally considered to be social animals, easily approaching and greeting unfamiliar mice.

But it seems that when strange mice are aggressive, a mouse over time becomes timid and withdrawn.

Giving the timid mice antidepressants such as Prozac improves their behavior, but so does deleting a gene called BDNF, which helps regulate the release of the neurotransmitter dopamine, a key substance that carries signals from one nerve cell to another, in the brain's reward pathway.

Dr. Nestler and his colleagues exposed mice to daily bouts of "social defeat," in which they encountered aggressive mice that overcame them in fights.

This training went on for 10 days.

The mice eventually became "defeated," no longer approaching unfamiliar mice, and four weeks later, the defeated mice still avoided other mice, not only their former bullies but even smaller and more docile mice.

However when given the antidepressant drugs Prozac or Tofranil, the defeated mice's social interaction improved.

Dr. Nestler says the important point is that the antidepressant worked over a long period, not just short-term, thus resembling human treatment.

The researchers hypothesized that the ventral tegmental area may be the source of BDNF in the nucleus accumbens and that this BDNF is important in shaping behavior. To test the theory, the researchers used viral gene transfer to delete the BDNF gene in the ventral tegmental area.

Mice lacking the gene did not become depressed when exposed to bullies, showing that BDNF signals from the ventral tegmental area to the nucleus accumbens are critical for animals to learn aspects of social experiences.

The loss of withdrawn behavior in mice lacking the BDNF gene echoes the behavior of mice treated with antidepressants, the researchers said.

Moreover, removal of the BDNF gene induced many of the same long-lasting changes in the nucleus accumbens as caused by chronic antidepressant treatment.

Deleting the molecule involved anesthetizing the mice, then injecting this very specific part of their brains with a virus that disables the molecule.

Berton says this kind of technique has been used experimentally in research into Parkinson's disease, and they believe that BDNF is essential in shaping changes in nerve pathways and behavior associated with social stress.

The next step says Dr.Berton, is to record the electrical activity of brain cells in the reward pathway in the mice as they undergo these tasks.