Yoon, Sujung Won, Woojin Lee, Suji Han, Kayoung Ha, Eunji Lee, Juheon Hyeon, Seung Jae Joo, Yoonji Hong, Haejin Lee, Hyangwon Song, Yumi Park, Ki Duk Huber, Bertrand R. Lee, Junghee Edden, Richard A. E. Suh, Minah Ryu, Hoon Lee, C. Justin Lyoo, In Kyoon 2025-08-20T07:06:31Z 2025-08-20T07:06:31Z 2025-08-20 2025-07 2095-9907 https://pubs.kist.re.kr/handle/201004/153001 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. English Nature Publishing Group | Sichuan University Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder Article 10.1038/s41392-025-02317-5 1 Signal Transduction and Targeted Therapy, v.10, no.1 Signal Transduction and Targeted Therapy 10 1 Y scie scopus 001537104400001 2-s2.0-105011850932 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article PREFRONTAL CORTEX MONOAMINE-OXIDASE TONIC INHIBITION GABA TRAUMA FEAR EXTINCTION VETERANS RECOVERY MODELS