Key Questions Answered
Q: Why do PTSD patients struggle to forget traumatic memories?
A: The study reveals that excessive GABA, produced by astrocytes via the MAOB enzyme, disrupts the brain’s ability to extinguish fear responses.
Q: What is KDS2010 and how does it help?
A: KDS2010 is a brain-penetrant MAOB inhibitor that reduced GABA levels, restored brain function, and reversed PTSD-like symptoms in mice.
Q: How was the link between clinical symptoms and brain chemistry established?
A: Researchers used a reverse translational approach, starting with brain scans of PTSD patients and tracing the dysfunction to astrocyte-derived GABA production.
Summary: A new study reveals that astrocyte-derived GABA, not neuronal activity, plays a central role in PTSD by impairing the brain’s ability to extinguish traumatic memories. Researchers found this excess GABA originates from the enzyme MAOB in astrocytes and disrupts fear regulation in the medial prefrontal cortex.
Using the MAOB inhibitor KDS2010, they successfully reversed PTSD-like symptoms in mice, restoring normal brain function. This work opens a novel path to treating PTSD through glial-targeted therapies, with promising human trial prospects.
Key Facts
- Astrocyte Role: Excess GABA from astrocytes, not neurons, impairs memory extinction in PTSD.
- Drug Discovery: KDS2010, a reversible MAOB inhibitor, normalized fear responses in mouse models.
- Reverse Translation: Clinical imaging guided lab discovery, linking human PTSD symptoms to cellular dysfunction.
Source: Institute for Basic Science
Did you know that patients with post traumatic stress disorder (PTSD) often struggle to forget traumatic memories, even long after the danger has passed?
This failure to extinguish fear memories has long puzzled scientists and posed a major hurdle for treatment, especially since current medications targeting serotonin receptors offer limited relief for only a subset of patients.
In a new discovery, scientists at the Institute for Basic Science (IBS) and Ewha Womans University have uncovered a new brain mechanism driving PTSD — and a promising drug that may counteract its effects.
Led by Dr. C. Justin LEE at the IBS Center for Cognition and Sociality and Professor LYOO In Kyoon at Ewha Womans University, the team has shown that excessive GABA (gamma-aminobutyric acid) produced by astrocytes, which are star-shaped support cells in the brain, impairs the brain’s ability to extinguish fear memories. This deficit is a core feature of PTSD and helps explain why traumatic memories can persist long after the threat has passed.
Crucially, the researchers found that a brain-permeable drug called KDS2010, which selectively blocks the monoamine oxidase B enzyme responsible for this abnormal GABA production, can reverse PTSD-like symptoms in mice. The drug has already passed Phase 1 safety trials in humans, making it a strong candidate for future PTSD treatments.
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.
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 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.
About this PTSD and neuropharmacology research news
Author: William Suh
Source: Institute for Basic Science
Contact: William Suh – Institute for Basic Science
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder” by C. Justin LEE et al. Signal Transduction and Targeted Therapy
Abstract
Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder
Post-traumatic stress disorder (PTSD) remains a debilitating psychiatric condition with limited pharmacological treatment options. Identifying novel therapeutic targets is critical for addressing its unmet clinical needs.
Through our comprehensive human clinical research, including both cross-sectional and longitudinal studies, we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid (GABA) levels and PTSD symptoms.
Notably, elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow (CBF) and symptom severity, normalizing with recovery, highlighting GABA dysregulation as a key mechanism in the disorder.
Postmortem and PTSD-like mouse models implicated monoamine oxidase B (MAOB)-dependent astrocytic GABA as a primary driver of this imbalance, exacerbating deficit in fear extinction retrieval.
Genetic and pharmacological inhibition of MAOB effectively restored astrocytic GABA and improved fear extinction retrieval in PTSD-like mouse models.
Specifically, KDS2010, a recently developed highly selective and reversible MAOB inhibitor, not only restored astrocytic GABA homeostasis but also rescued CBF deficits and reduced tonic GABA and astrogliosis in the prefrontal cortex.
Moreover, KDS2010 successfully advanced through Phase 1 clinical trials, showing a favorable safety profile and paving the way for Phase 2 trials to evaluate its therapeutic potential in PTSD.
Our findings highlight the pivotal role of astrocytic GABA in PTSD pathophysiology and establish MAOB inhibition as a mechanistically targeted approach to alleviate symptoms.
By bridging human and animal studies with translational clinical trials, this work positions KDS2010 as a promising first-in-class therapy, offering a novel paradigm for PTSD treatment.
