Posts tagged GABA neurons

Findings Point to New Potential Drug Target—GABA Neurons—to Treat Patients with Depression and Other Mood Disorders

A new drug target to treat depression and other mood disorders may lie in a group of GABA neurons (gamma-aminobutyric acid –the neurotransmitters which inhibit other cells) shown to contribute to symptoms like social withdrawal and increased anxiety, Penn Medicine researchers report in a new study in the Journal of Neuroscience.

Experts know that people suffering from depression and other mood disorders often react to rejection or bullying by withdrawing themselves socially more than the average person who takes it in strides, yet the biological processes behind these responses have remained unclear.

Now, a preclinical study, from the labs of Olivier Berton, PhD, an assistant professor in the department of Psychiatry, with Collin Challis of the Neuroscience Graduate Group, and Sheryl Beck, PhD, a professor in the department of Anesthesiology at Children’s Hospital of Philadelphia, found that bullying and other social stresses triggered symptoms of depression in mice by activating GABA neurons, in a never-before-seen direct relationship between social stimuli and this neural circuitry.  Activation of those neurons, they found, directly inhibited levels of serotonin, long known to play a vital role in behavioral responses—without it, a depressed person is more likely to socially withdrawal.

 Conversely, when the researchers successfully put the brake on the GABA neurons, mice became more resilient to bullying and didn’t avoid once -perceived threats.

“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.”

Less serotonin elicits socially defensive responses such as avoidance or submission, where enhancement—the main goal of antidepressants—induces a positive shift in the perception of socio-affective stimuli, promoting affiliation and dominance. However, current antidepressants targeting serotonin, like SSRIs, are only effective in about 50 percent of patients. 

These new findings point to GABA neurons as a new, neural drug target that could help treat the other patients who don’t respond to today’s treatment.

For the study, “avoidant” mice were exposed to brief bouts of aggression from trained “bully” mice. By comparing gene expression in the brains of resilient and avoidant mice, Berton and colleagues discovered that bullying in avoidant mice puts GABA neurons in a state where they become more excitable and the mice exhibit signs of social defeat. Resilient mice, however, had no change in neuron levels and behavior.

To better understand the link between GABA and the development of stress resilience, Berton, Beck, and colleagues also devised an approach to directly manipulate levels: Lifting GABA inhibition of serotonin neurons reduced social and anxiety symptoms in mice exposed to bullies and also fully prevented neurobiological changes due to stress.

“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,” said Berton. “This has important implications for the understanding and treatment of mood disorders.”

(Source: uphs.upenn.edu)

Neuropathic pain — pain that results from a malfunction in the nervous system — is a daily reality for millions of Americans. Unlike normal pain, it doesn’t go away after the stimulus that provoked it ends, and it also behaves in a variety of other unusual and disturbing ways. Someone suffering from neuropathic pain might experience intense discomfort from a light touch, for example, or feel as though he or she were freezing in response to a slight change in temperature.

A major part of the answer to the problem of neuropathic pain, scientists believe, is found in spinal nerve cells that release a signaling chemical known as GABA. These GABA neurons act as a sort of brake on pain impulses; it’s thought that when they die or are disabled the pain system goes out of control. If GABA neurons could be kept alive and healthy after peripheral nerve or tissue injury, it’s possible that neuropathic pain could be averted.

Now, University of Texas Medical Branch at Galveston researchers have found a way to, at least partially, accomplish this objective. The key, they determined, is stemming the biochemical assault by reactive oxygen species that are generated in the wake of nerve injury.

"GABA neurons are particularly susceptible to oxidative stress, and we hypothesized that reactive oxygen species contribute to neuropathic sensitization by promoting the loss of GABA neurons as well as hindering GABA functions," said UTMB professor Jin Mo Chung, senior author of a paper on the research now online in the journal Pain.

To test this hypothesis — and determine whether GABA neurons could be saved — the researchers conducted a series of experiments in mice that had been surgically altered to simulate the conditions of neuropathic pain. In one key experiment, mice treated with an antioxidant compound for a week after surgery were compared with untreated mice. The antioxidant mice showed less pain-associated behavior and were found to have far more GABA neurons than the untreated mice.

"So by giving the antioxidant we lowered the pain behavior, and when we look at the spinal cords we see the GABA neuron population is almost the same as normal," Chung said. "That suggested we prevented those neurons from dying, which is a big thing."

One complication, Chung noted, is a “moderate quantitative mismatch” between the behavioral data and the GABA-neuron counts. While the anti-oxidant mice displayed less pain behavior, their behavioral improvement wasn’t as substantial as their high number of GABA neurons would suggest. One possibility is that the surviving neurons were somehow impaired — a hypothesis supported by electrophysiological data.

Although no clinical trials are planned in the immediate future, Chung believes anti-oxidants have great potential as a treatment for neuropathic pain. “If this is true and it works in humans — well, any time you can salvage neurons, it’s a good thing,” he said. “Neuropathic pain is very difficult to treat, and I think this is a possibility, a good possibility.”

(Source: eurekalert.org)