RESUMEN
INTRODUCTION: Traumatic 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. AIM: In this study, we investigated the expression, regulation and biological function of Arc in both in vivo and in vitro experimental TBI models. RESULTS: Traumatic 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. CONCLUSION: In 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.
