Excessive levels of GABA released by astrocytes impair the brain's ability to extinguish fear responses in PTSD, but a newly identified drug target offers promising hope for treatment.

Many people with post-traumatic stress disorder (PTSD) continue to relive painful memories long after the actual threat is gone. Their brains seem unable to let go of fear, a phenomenon that has long puzzled scientists and made effective treatment difficult. Current medications that target serotonin receptors often provide only limited relief, and usually help just a fraction of those affected.

Now, researchers from the Institute for Basic Science (IBS) and Ewha Womans University have identified a previously unknown brain process that may be responsible for this persistent fear response. They have also found a potential treatment that could change how PTSD is managed.

The study, led by Dr. C. Justin LEE from the IBS Center for Cognition and Sociality and Professor LYOO In Kyoon from Ewha Womans University, discovered that astrocytes (star-shaped support cells in the brain) can produce too much GABA (gamma-aminobutyric acid). This excess GABA interferes with the brain's ability to suppress fear-related memories, a key difficulty for people with PTSD.

Importantly, the team tested a drug called KDS2010 that crosses the blood-brain barrier and specifically blocks the monoamine oxidase B enzyme, which drives this abnormal GABA production. In mouse models, the drug was able to reduce PTSD-like symptoms. KDS2010 has already completed Phase 1 human safety trials, positioning it as a promising option for future PTSD treatment.

High GABA Levels and Reduced Brain Activity

PTSD remains difficult to treat, with current medications targeting serotonin pathways providing limited relief for many patients. The new study focused on the medial prefrontal cortex (mPFC), a region of the brain critical for regulating fear, and found that PTSD patients had unusually high levels of GABA and reduced cerebral blood flow in this area. These findings emerged from brain imaging studies of more than 380 participants. Importantly, GABA levels decreased in patients who showed clinical improvement, pointing to the chemical's central role in recovery.

Astrocyte Derived GABA and Therapeutic Effects of KDS2010 in PTSD
Astrocyte-Derived GABA and Therapeutic Effects of KDS2010 in PTSD. Brain imaging of PTSD patients revealed unusually high levels of GABA and reduced cerebral blood flow in the prefrontal cortex, showing that changes strongly correlated with symptom severity. In animal models, this excess GABA was traced to reactive astrocytes producing it abnormally due to increased MAOB and reduced levels of the GABA-degrading enzyme ABAT. This disrupted normal brain function and impaired the ability to extinguish fear. Treatment with KDS2010, a selective MAOB inhibitor, successfully lowered astrocytic GABA, restored brain activity, and rescued fear extinction, highlighting its potential as a therapeutic option. Credit: Institute for Basic Science

To uncover the origin of this excess GABA, the researchers examined postmortem human brain tissue and used PTSD-like mouse models. They discovered that astrocytes, not neurons, were producing abnormal amounts of GABA via the enzyme monoamine oxidase B (MAOB). This astrocyte-derived GABA impaired neural activity, blocking the brain's ability to forget traumatic memories.

When the researchers administered KDS2010, a highly selective, reversible MAOB inhibitor developed at IBS, the mice showed normalized brain activity and were able to extinguish fear responses. The drug reduced GABA levels, restored blood flow in the mPFC, and re-enabled memory extinction mechanisms. The study thus confirms astrocytic MAOB as a central driver of PTSD symptoms, and MAOB inhibition as a viable therapeutic path.

A Reverse Translational Approach

A major challenge of the study was linking clinical findings in humans with cellular mechanisms in the lab. The researchers addressed this by applying a "reverse translational" strategy: they began with clinical brain scans and moved backward to identify the cellular source of dysfunction, then confirmed the mechanism and tested drug effects in animal models. This approach led to a new understanding of how glial cells — long thought to be passive — actively shape psychiatric symptoms.

"This study is the first to identify astrocyte-derived GABA as a key pathological driver of fear extinction deficit in PTSD," said Dr. WON Woojin, a postdoctoral researcher and co-first author of the study. "Our findings not only uncover a novel astrocyte-based mechanism underlying PTSD, but also provide preclinical evidence for a new therapeutic approach using an MAOB inhibitor."

Director C. Justin LEE, who led the study, emphasized that "This work represents a successful example of reverse translational research, where clinical findings in human guided the discovery of underlying mechanisms in animal models. 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."

The researchers plan to further investigate astrocyte-targeted therapies for various neuropsychiatric disorders. With KDS2010 currently undergoing Phase 2 clinical trials, this discovery may soon lead to new options for patients whose symptoms have not responded to conventional treatments.

Reference: "Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder" by Sujung Yoon, Woojin Won, Suji Lee, Kayoung Han, Eunji Ha, Juheon Lee, Seung Jae Hyeon, Yoonji Joo, Haejin Hong, Hyangwon Lee, Yumi Song, Ki Duk Park, Bertrand R. Huber, Junghee Lee, Richard A. E. Edden, Minah Suh, Hoon Ryu, C. Justin Lee and In Kyoon Lyoo, 28 July 2025, Signal Transduction and Targeted Therapy.
DOI: 10.1038/s41392-025-02317-5

Funding: Institute for Basic Science

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