Metabotropic glutamate receptor 5 promotes blood-brain barrier recovery after traumatic brain injury

• Published in: Experimental neurology 2024-04, Vol.374, p.114691-114691, Article 114691
• Main Authors: Ren, Jiakui, Yang, Teng, Liu, Heting, Ma, Pengjiao, Zhou, Mi, Li, Jiabo, Li, Tao, Sun, Jianbin, He, Wenhui, Xu, Lunshan, Dai, Shuang-Shuang, Liu, Yang-Wuyue
• Format: Article
• Language: English
• Subjects: ACTN1; Blood brain barrier; mGluR5; Traumatic brain injury
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2024.114691

Blood-brain barrier (BBB) impairment and glutamate release are two pathophysiological features of traumatic brain injury (TBI), contributing to secondary brain damage and neuroinflammation. However, our knowledge of BBB integrity damage and dysfunction are still limited due to the diverse and fluctuating expression of glutamate receptors after trauma. Here, we confirmed the downregulation of metabotropic glutamate receptor 5 (mGluR5) on microvascular endothelial cell within the acute phase of TBI, and the recovered mGluR5 levels on BBB was positively associated with blood perfusion and neurological recovery. In whole body mGluR5-knockout mice, BBB dysfunction and neurological deficiency were exacerbated after TBI compared with wild type mice. In terms of mechanism, the amino acid sequence 201–259 of cytoskeletal protein Alpha-actinin-1 (ACTN1) interacted with mGluR5, facilitating mGluR5 translocation from cytoplasmic compartment to plasma membrane in endothelial cells. Activation of plasma membrane mGluR5 triggers the PLC/PKCμ/c-Jun signaling pathway, leading to increased expression of the tight junction-actin cytoskeleton connecting protein zonula occludens-1 (ZO-1). Our findings uncover a novel mechanism mediated by membrane and cytoplasmic mGluR5 in endothelial cell integrity maintenance and repair, providing the potential therapeutic target for TBI treatment targeting at mGluR5 and mGluR5/ACTN1 complex in BBB. In cerebrovascular endothelial cell, mGluR5/ACTN-1 complex facilitates membrane mGluR5 location. Activation membrane mGluR5 promotes ZO-1 expression in PLC/PKCμ/c-Jun dependent manner. TBI leads to cytoplasmic mGluR5/ACTN-1 disassociation and membrane mGluR5 downregulation, jeopardizing BBB integrity subsequently. [Display omitted] •mGluR5 expression is fundamental for BBB recovery after TBI.•mGluR5/ACTN1 complex facilitates mGluR5 cellular membrane translocation in endothelial cell.•Activating membrane mGluR5 promotes ZO-1 expression through PLC/PKCμ/c-Jun pathway.