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Article

Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury

1
Department of Forensic Clinical Medicine, School of Forensic Medicine, China Medical University, Shenyang 110122, China
2
Key Laboratory of Forensic Bio-Evidence Science, Shenyang 110122, China
3
China Medical University Center of Forensic Investigation, Shenyang 110122, China
4
Anshan Public Security Bureau, Anshan 114031, China
5
First Clinical College, China Medical University, Shenyang 110001, China
*
Authors to whom correspondence should be addressed.
Biomolecules 2025, 15(10), 1408; https://doi.org/10.3390/biom15101408
Submission received: 30 July 2025 / Revised: 27 September 2025 / Accepted: 1 October 2025 / Published: 2 October 2025

Abstract

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.
Keywords: TBI; 2-AG; GLT-1; CREB; astrocyte TBI; 2-AG; GLT-1; CREB; astrocyte

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MDPI and ACS Style

Bu, B.; Ma, R.; Wang, C.; Jiang, S.; Xu, X. Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury. Biomolecules 2025, 15, 1408. https://doi.org/10.3390/biom15101408

AMA Style

Bu B, Ma R, Wang C, Jiang S, Xu X. Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury. Biomolecules. 2025; 15(10):1408. https://doi.org/10.3390/biom15101408

Chicago/Turabian Style

Bu, Bin, Ruiyao Ma, Chengyu Wang, Shukun Jiang, and Xiaoming Xu. 2025. "Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury" Biomolecules 15, no. 10: 1408. https://doi.org/10.3390/biom15101408

APA Style

Bu, B., Ma, R., Wang, C., Jiang, S., & Xu, X. (2025). Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury. Biomolecules, 15(10), 1408. https://doi.org/10.3390/biom15101408

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