Astrocytes, Not Neurons, Identified as Key Drivers of PTSD

For people with post-traumatic stress disorder (PTSD), fear doesn’t fade. Now, a team from the Institute for Basic Science and Ewha Womans University may have found out why.

The new study, published in Signal Transduction and Targeted Therapy, identified a surprising culprit: brain support cells  called astrocytes. The researchers showed that a drug, now involved in clinical trials, targeting these cells reversed PTSD-like symptoms in mice.

What brain changes are linked to PTSD symptoms

PTSD is characterized by persistent and intrusive traumatic memories. A core feature is the failure to extinguish fear, meaning the brain continues to respond as if a threat is present, even when it is not.

Current treatments are limited. Serotonin-based medications are the main option; however, only a minority of patients achieve full remission. There has been little progress in understanding why fear extinction breaks down at a biological level.

“PTSD remains a debilitating psychiatric condition with limited pharmacological treatment options. Identifying novel therapeutic targets is critical for addressing its unmet clinical needs,” said the authors of the recent study.

One target of interest is gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that helps regulate brain activity. The medial prefrontal cortex (mPFC), which plays a key role in fear regulation, relies on GABA to suppress overactive fear responses. Imaging studies have shown elevated GABA levels in the mPFC in people with PTSD, although the source and mechanism behind this imbalance remain unclear.

Recent work has focused on astrocytes, non-neuronal cells traditionally viewed as support cells, and they are increasingly recognized as active regulators of brain signaling.

The new study aimed to identify the source of abnormal GABA in PTSD and test whether reducing it could restore normal fear processing.

How astrocytes contribute to PTSD in humans and mice

The team used a multi-stage approach across human and animal models to identify the role of astrocytic GABA in PTSD. The researchers combined brain imaging in living participants, postmortem brain tissue analysis, genetic interventions in mice and drug testing.

In clinical studies, PTSD patients showed elevated GABA levels and reduced cerebral blood flow in the mPFC, abnormalities that were not seen in recovered patients. A separate longitudinal study confirmed that GABA levels declined over time in individuals whose symptoms improved.

Postmortem analysis of human brain tissue identified that the likely source of excess GABA was from astrocytes in the mPFC. These cells showed increased expression of the enzyme monoamine oxidase B (MAOB) – which produces GABA – and reduced levels of 4-aminobutyrate aminotransferase – which breaks it down.

In a mouse model of PTSD, similar changes were seen – astrocytic GABA was elevated, neurons were less responsive and mice had trouble extinguishing fear responses.

Instead of acting in quick bursts, this GABA created constant, low-level inhibition that dampened the brain activity needed to suppress fear responses.

Knocking down MAOB in astrocytes corrected these effects.

The researchers then tested KDS2010, a selective MAOB inhibitor. In mice, it restored GABA balance, improved blood flow, reduced fear behaviors and reversed memory deficits. It also restored dopamine signaling, which may further support recovery.

Targeting astrocytic GABA for future PTSD treatments

KDS2010 has already completed Phase 1 safety trials in humans and is now a strong candidate for clinical trials in PTSD.

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The study shifts attention away from neurons and toward glial cells, especially astrocytes, as active drivers of psychiatric symptoms.

“This study is the first to identify astrocyte-derived GABA as a key pathological driver of fear extinction deficit in PTSD,” said co-lead author Dr. Won Woojin, a postdoctoral researcher at the Institute for Basic Science.

A Phase 2 clinical trial of KDS2010 is underway. The team is also investigating related pathways, such as polyamine metabolism, and extending their studies to brain regions including the hippocampus and amygdala.

“This work represents a successful example of reverse translational research, where clinical findings in humans guided the discovery of underlying mechanisms in animal models,” said co-corresponding author Dr. Changjoon Justin Lee, a neuroscientist and co-director of the Center for Cognition and Sociality at the Institute for Basic Science.

“By identifying astrocytic GABA as a pathological driver in PTSD and targeting it via MAOB inhibition, the study opens a completely new therapeutic paradigm not only for PTSD but also for other neuropsychiatric disorders such as panic disorder, depression and schizophrenia,” he added.

Reference: Yoon S, Won W, Lee S, et al. Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder. Sig Transduct Target Ther. 2025;10(1):240. doi: 10.1038/s41392-025-02317-5

This article is a rework of a press release issued by the Institute for Basic Science. Material has been edited for length and content.