Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder
Abstract 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 cro...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02317-5 |
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| author | 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 In Kyoon Lyoo |
| author_facet | 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 In Kyoon Lyoo |
| author_sort | Sujung Yoon |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-522f243af9d8460cb35fad66619eb989 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-522f243af9d8460cb35fad66619eb9892025-08-20T03:41:57ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-07-0110111910.1038/s41392-025-02317-5Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorderSujung Yoon0Woojin Won1Suji Lee2Kayoung Han3Eunji Ha4Juheon Lee5Seung Jae Hyeon6Yoonji Joo7Haejin Hong8Hyangwon Lee9Yumi Song10Ki Duk Park11Bertrand R. Huber12Junghee Lee13Richard A. E. Edden14Minah Suh15Hoon Ryu16C. Justin Lee17In Kyoon Lyoo18Ewha Brain Institute, Ewha Womans UniversityCenter for Cognition and Sociality, Institute for Basic Science (IBS)Division of Psychology and Cognitive Science, Seoul Women’s UniversityBiomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan UniversityEwha Brain Institute, Ewha Womans UniversityCenter for Neuroscience Imaging Research, Institute for Basic Science (IBS)Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST)Ewha Brain Institute, Ewha Womans UniversityEwha Brain Institute, Ewha Womans UniversityEwha Brain Institute, Ewha Womans UniversityEwha Brain Institute, Ewha Womans UniversityCenter for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST)VA Boston Healthcare System, U.S. Department of Veteran AffairsVA Boston Healthcare System, U.S. Department of Veteran AffairsThe Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of MedicineCenter for Neuroscience Imaging Research, Institute for Basic Science (IBS)Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST)Center for Cognition and Sociality, Institute for Basic Science (IBS)Ewha Brain Institute, Ewha Womans UniversityAbstract 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.https://doi.org/10.1038/s41392-025-02317-5 |
| spellingShingle | 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 In Kyoon Lyoo Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder Signal Transduction and Targeted Therapy |
| title | Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder |
| title_full | Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder |
| title_fullStr | Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder |
| title_full_unstemmed | Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder |
| title_short | Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder |
| title_sort | astrocytic gamma aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder |
| url | https://doi.org/10.1038/s41392-025-02317-5 |
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