Serotonin is 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 it is not yet well understood how this happens. Antidepressants known as SSRIs (selective serotonin reuptake inhibitors) have been developed to increase levels of serotonin in the brain. They have proven effective at alleviating symptoms of depression in about 50 percent of patients. The other approximate 50 percent do not respond.
Senior author of a new study, and two-time NARSAD Grantee, Olivier Berton, Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, in collaboration with Sheryl Beck, Ph.D., at Children’s Hospital of Philadelphia, has found a new potential target to treat the behavioral symptoms of depression: GABA neurons (a class of neurons that inhibits other cells). The research results were published August 28th in the Journal of Neuroscience.
“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,” said Dr. Berton. “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.”
In a research project supported by his 2008 NARSAD Young Investigator Grant, Dr. Berton and his graduate student Collin Challis exposed mice to short periods of aggression from “bully” mice. They then studied a subset of the bullied mice that became excessively avoidant. This avoidance behavior resembles the behavior exhibited by people suffering from affective disorders, who often withdraw more than the average person when facing social pressures like criticism or rejection. By measuring electrical activity and protein expression in the brains of avoidant mice, they found their GABA neurons entered a state where they became overly excitable and started “putting a brake” on nearby serotonin neurons. Resilient mice, however, which remain socially interactive, did not show this change.
The researchers then employed a technique called optogenetics (learn more about optogenetics) to temporarily silence the overactive GABA neurons. Observing the resulting effect of this brief “light treatment” on the behavior of bullied mice, they found that lifting the brake on serotonin cells for a short period precisely timed with the periods of bullying was sufficient to fully prevent the development of avoidance symptoms.
"Our results provide a novel cellular understanding of how social defensiveness and social withdrawal develop in mice and gives us a stepping stone to better understand the basis of similar social symptoms in humans," said Dr. Berton. “This has important implications for the understanding and treatment of mood disorders."
Other NARSAD Grantees that participated in this study include Julie C.M. Espallergues, Ph.D., (2010, NARSAD Young Investigator Grantee) and R. Christopher Pierce, Ph.D., (1997, 1999 NARSAD Young Investigator Grantee).
Read the abstract of this research