From The Quarterly, Winter 2014

In research initiated with the support of a 2008 NARSAD Young Investigator Grant, Olivier Berton, Ph.D., led a team that has found what may be a new target for treating symptoms of depression: GABA neurons, nerve cells that produce GABA (gamma-aminobutyric acid), a neurotransmitter that inhibits the activity of other cells.

Dr. Berton and collaborator Sheryl Beck, Ph.D., of Children’s Hospital of Philadelphia, published the results of their study August 28, 2013 in the Journal of Neuroscience.

At present, the most commonly prescribed antidepressant medications are SSRIs (selective serotonin reuptake inhibitors), which increase brain levels of serotonin, a neurotransmitter long known to play a key role in depression and other mood and anxiety disorders, including social phobia. Low levels of serotonin in the brain influence the way we perceive others and make us less prone to engage in social interaction. But SSRIs alleviate symptoms of depression in only about 50 percent of patients, for reasons that have not been understood.

In the reported study, Dr. Berton and his colleagues, including graduate student Collin Challis, exposed mice to short periods of aggression from “bully” mice. They then studied a subset of the mice that became excessively socially avoidant as a consequence of the bullying. Their behavior resembled behavior exhibited by people with affective disorders who withdraw when facing social pressures. In previous studies Dr. Berton has shown that these behavioral symptoms can be reversed by longterm treatment with antidepressants.

To understand what is happening in the brains of these mice as symptoms arise (or not), the researchers measured electrical and biochemical indices of neuronal activity. They found that in the extremely avoidant mice, a specific population of neurons located in the brainstem that release GABA, the main inhibitory neurotransmitter in the nervous system, entered an overly excitable state and began shutting down the activity of nearby serotonin neurons. In contrast, resilient mice that remained socially interactive did not exhibit this GABAergic sensitization (and serotonin neurons were not shut down). The researchers then used the new technology optogenetics to temporarily silence the overactive GABA neurons and found that lifting the brake on the serotonin cells for periods that were precisely timed with the periods of bullying was sufficient to prevent development of avoidance symptoms.

“This is the first time that GABA neuron activity—found deep in the brainstem—has been shown to play a key role in the cognitive processes associated with social approach or avoidance behavior in mammals,” Dr. Berton says. “The results point to a new direction to understand why current antidepressants, which are used to treat depression and social phobia, may not work for everyone and how to make them work better, by targeting GABA neurons that put the brake on serotonin cells.”