The mGluR5‐mediated Arc activation protects against experimental traumatic brain injury in rats

Abstract

AbstractIntroductionTraumatic brain injury (TBI) is a complex pathophysiological process, and increasing attention has been paid to the important role of post‐synaptic density (PSD) proteins, such as glutamate receptors. Our previous study showed that a PSD protein Arc/Arg3.1 (Arc) regulates endoplasmic reticulum (ER) stress and neuronal necroptosis in traumatic injury in vitro.AimIn this study, we investigated the expression, regulation and biological function of Arc in both in vivo and in vitro experimental TBI models.ResultsTraumatic neuronal injury (TNI) induced a temporal upregulation of Arc in cortical neurons, while TBI resulted in sustained increase in Arc expression up to 24 h in rats. The increased expression of Arc was mediated by the activity of metabotropic glutamate receptor 5 (mGluR5), but not dependent on the intracellular calcium (Ca2+) release. By using inhibitors and antagonists, we found that TNI regulates Arc expression via Gq protein and protein turnover. In addition, overexpression of Arc protects against TBI‐induced neuronal injury and motor dysfunction both in vivo and in vitro, whereas the long‐term cognitive function was not altered. To determine the role of Arc in mGluR5‐induced protection, lentivirus‐mediated short hairpin RNA (shRNA) transfection was performed to knockdown Arc expression. The mGluR5 agonist (RS)‐2‐chloro‐5‐hydroxyphenylglycine (CHPG)‐induced protection against TBI was partially prevented by Arc knockdown. Furthermore, the CHPG‐induced attenuation of Ca2+ influx after TNI was dependent on Arc activation and followed regulation of AMPAR subunits. The results of Co‐IP and Ca2+ imaging showed that the Arc‐Homer1 interaction contributes to the CHPG‐induced regulation of intracellular Ca2+ release.ConclusionIn summary, the present data indicate that the mGluR5‐mediated Arc activation is a protective mechanism that attenuates neurotoxicity following TBI through the regulation of intracellular Ca2+ hemostasis. The AMPAR‐associated Ca2+ influx and ER Ca2+ release induced by Homer1‐IP3R pathway might be involved in this protection.