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

CNS Neurosci Ther. 2024 Aug;30(8):e14695. doi: 10.1111/cns.14695.

Abstract

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.

Keywords: Arc; glutamate receptor; mGluR5; post‐synaptic density; traumatic brain injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries, Traumatic* / metabolism
  • Brain Injuries, Traumatic* / pathology
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebral Cortex / metabolism
  • Cytoskeletal Proteins* / biosynthesis
  • Cytoskeletal Proteins* / genetics
  • Cytoskeletal Proteins* / metabolism
  • Disease Models, Animal
  • Glycine / analogs & derivatives
  • Homer Scaffolding Proteins* / metabolism
  • Male
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Neurons* / drug effects
  • Neurons* / metabolism
  • Phenylacetates
  • Rats
  • Rats, Sprague-Dawley*
  • Receptor, Metabotropic Glutamate 5* / antagonists & inhibitors
  • Receptor, Metabotropic Glutamate 5* / metabolism

Substances

  • Receptor, Metabotropic Glutamate 5
  • activity regulated cytoskeletal-associated protein
  • Nerve Tissue Proteins
  • Cytoskeletal Proteins
  • Grm5 protein, rat
  • Homer Scaffolding Proteins
  • Homer1 protein, rat
  • 2-chloro-5-hydroxyphenylglycine
  • Calcium
  • Glycine
  • Phenylacetates