{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T06:03:26Z","timestamp":1791612206159,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the project of the Education Department of Liaoning Province","award":["JYTMS20230126"],"award-info":[{"award-number":["JYTMS20230126"]}]},{"name":"the Key Laboratory of Forensic Bio-evidence Science of Liaoning Province","award":["2023-PYKT-004)"],"award-info":[{"award-number":["2023-PYKT-004)"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Glutamate transporter 1 (GLT-1) plays a vital role in maintaining glutamate homeostasis in the body. A decreased GLT-1 expression in astrocytes can heighten neuronal sensitivity to glutamate excitotoxicity after traumatic brain injury (TBI). Despite its significance, the mechanisms behind the reduced expression of GLT-1 following TBI remain poorly understood. After TBI, the endocannabinoid 2-arachidonoyl glycerol (2-AG) is elevated several times. 2-AG is known to inhibit key positive transcriptional regulators of GLT-1. This study aims to investigate the role of 2-AG in regulating GLT-1 expression and to uncover the underlying mechanisms involved. Methods: A controlled cortical impact (CCI) model was used to establish a TBI model in C57BL\/6J mice. The CB1 receptor antagonist (referred to as AM281) and the monoacylglycerol lipase (MAGL) inhibitor (referred to as JZL184) were administered to investigate the role and mechanism of 2-AG in regulating GLT-1 expression following TBI. Behavioral tests were conducted to assess neurological functions, including the open field, Y-maze, and novel object recognition tests. Apoptotic cells were identified using the TUNEL assay, while Western blot analysis and immunofluorescence were employed to determine protein expression levels. Results: The expression of GLT-1 in the contused cortex and hippocampus following TBI showed an initial decrease, followed by a gradual recovery. It began to decrease within half an hour, reached its lowest level at 2 h, and then gradually increased, returning to normal levels by 7 days. The administration of AM281 alleviated neuronal death, improved cognitive function, and reversed the reduction of GLT-1 caused by TBI in vivo. Furthermore, 2-AG decreased GLT-1 expression in astrocytes through the CB1-CREB signaling pathway. Mechanistically, 2-AG activated CB1, which inhibited CREB phosphorylation in astrocytes. This decreased GLT-1 levels and ultimately increased neuronal sensitivity to glutamate excitotoxicity. Conclusions: Our research demonstrated that the upregulation of GLT-1 expression effectively mitigated neuronal apoptosis and cognitive dysfunction by inhibiting the CB1-CREB signaling pathway. This finding may offer a promising therapeutic strategy for TBI.<\/jats:p>","DOI":"10.3390\/biom15101408","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T15:07:48Z","timestamp":1759417668000},"page":"1408","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury"],"prefix":"10.3390","volume":"15","author":[{"given":"Bin","family":"Bu","sequence":"first","affiliation":[{"name":"Department of Forensic Clinical Medicine, School of Forensic Medicine, China Medical University, Shenyang 110122, China"},{"name":"Key Laboratory of Forensic Bio-Evidence Science, Shenyang 110122, China"},{"name":"China Medical University Center of Forensic Investigation, Shenyang 110122, China"},{"name":"Anshan Public Security Bureau, Anshan 114031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiyao","family":"Ma","sequence":"additional","affiliation":[{"name":"First Clinical College, China Medical University, Shenyang 110001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Forensic Clinical Medicine, School of Forensic Medicine, China Medical University, Shenyang 110122, China"},{"name":"Key Laboratory of Forensic Bio-Evidence Science, Shenyang 110122, China"},{"name":"China Medical University Center of Forensic Investigation, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shukun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Forensic Clinical Medicine, School of Forensic Medicine, China Medical University, Shenyang 110122, China"},{"name":"Key Laboratory of Forensic Bio-Evidence Science, Shenyang 110122, China"},{"name":"China Medical University Center of Forensic Investigation, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Forensic Clinical Medicine, School of Forensic Medicine, China Medical University, Shenyang 110122, China"},{"name":"Key Laboratory of Forensic Bio-Evidence Science, Shenyang 110122, China"},{"name":"China Medical University Center of Forensic Investigation, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.neuropharm.2018.09.032","article-title":"Combination of drug and stem cells neurotherapy: Potential interventions in neurotrauma and traumatic brain injury","volume":"145","author":"Zibara","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.neuint.2005.12.001","article-title":"Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury","volume":"48","author":"Yi","year":"2006","journal-title":"Neurochem. 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