Targeting GABA Neurons Offers Clues for Boosting Resilience

Shutting off GABA neurons makes "bullied" mice more confident and resilient.

Posted Aug 31, 2013

Researchers at the University of Pennsylvania say they have discovered a “never-before-seen” direct relationship between social stimuli and the neural circuitry of GABA neurons and serotonin. Their findings point to a potential drug target aimed at GABA neurons (gamma-aminobutyric acid — the neurotransmitters which inhibit other cells) to treat depression and other mood disorders.

GABA neurons have previously been shown to contribute to symptoms like social withdrawal and increased anxiety. The Penn Medicine researcher's study is titled, “Raphe GABAergic Neurons Mediate the Acquisition of Avoidance after Social Defeat" and is published in the August 28, 2013 Journal of Neuroscience.

This study provides new clues on the biology behind why people who are suffering from depression and other mood disorders often react to being bullied by becoming socially withdrawn and disconnecting from friends and family. Until now, the biological processes of why some people are more resilient to bullying have been unclear.

In a pre-clinical study, Olivier Berton, PhD, an assistant professor in the Penn department of Psychiatry, and colleagues have found that bullying and other social stresses can trigger symptoms of depression in mice through the activation of GABA neurons.

GABA is the main inhibitory neurotransmitter in the central nervous system (CNS). GABAergic inhibition is seen at all levels of the CNS, including the hypothalamus, hippocampus, cerebral cortex and cerebellar cortex. GABA interneurons are ubiquitous in the brain. Fifty-percent of the inhibitory synapses in the brain are controlled by GABA.

Activation of GABA neurons directly inhibited levels of serotonin, which has long been known to play a key role in behavioral responses to social situations. Like every neurotransmitter, the function of serotonin is complex and often overly generalized. That said, it is believed that lower levels of serotonin lead a depressed person to become more socially withdrawn.

Interestingly, when the Penn researchers successfully put the brakes on the GABA neurons, mice became more resilient to bullying and didn't avoid threats that previously caused them to recoil in fear and isolate.

Reducing GABA > Increases Serotonin > Bolsters Resilience

Low levels of serotonin are believed to make people socially defensive and are linked to avoidance behavior and submission. The enhancement of serotonin creates an upward spiral and positive shift in the perception of socio-affective stimuli, and leads to feelings of connectedness affiliation — and potential dominance.

"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 help us to understand why current antidepressants may not work for everyone and how to make them work better – by targeting GABA neurons that put the brake on serotonin cells."

Scientist have been baffled as to why antidepressants that target serotonin (like SSRI’s) only reduce depression in about half the population. These new findings point to GABA neurons as a possible drug target that could offer new pharmaceutical options for patients who don't respond to current classes of antidepressants.

For the study, "avoidant" mice were exposed to brief bouts of aggression from genetically trained "bully" mice. By comparing the gene expression in the brains of resilient and avoidant mice, Berton and colleagues discovered that when avoidant mice were bullied their GABA neurons went into an excited state that increased avoidance behavior and social defeat.

Resilient mice showed no change in GABA neuron levels. The resilient mice maintained higher levels of serotonin and did not retreat when confronted by a threat from the “bully” mice.

To better understand the link between GABA and the development of stress resilience, Berton and colleagues used an advanced optogenetics-based approach to directly manipulate levels of specific neurotransmitters. They found that blocking GABA created a chain reaction that boosted serotonin neurons and reduced social and anxiety symptoms in mice exposed to bullies. Blocking GABA also fully prevented neurobiological changes due to social stress.

Conclusion: Are drugs the only way to alter GABA and boost resilience?

Berton concludes, "Our paper provides 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. This has important implications for the understanding and treatment of mood disorders."

But what is the sweet spot between being a “bully” mouse, a “resilient” mouse or an “avoidant” mouse? Would it be possible to fine-tune the perfect balance of a GABA reducing drug to make a human being just resilient enough, but not turn that person into a dominant bully? Probably. However, the potential for an individual to take high doses of such a pill could backfire by creating dominant "Master of Universe" mentalities en masse.

Studies like this offer interesting clues on ways that pharmaceuticals can improve our lives, but it's always important to proceed with caution when developing drugs that tamper with brain chemistry. Luckily, you can enter a neurobiological feedback loop from many angles. You can use mindset and behavior to change the balance of neurotransmitters in your brain. Obviously, within the spectrum of mood disorders, depression, and mental health sometimes medication is the best remedy. 

For more practical advice on how daily lifestyle choices improve your mind, body and brain please check out my Psychology Today blogs: "What Makes Some People More Resilient?", "Positive Actions Build Social Capital and Resilience" and "Decoding the Neuroscience of Fear and Fearlessness."

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