G protein-coupled receptor kinase 2 and group i metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration

Vincent Degos, Stéphane Peineau, Cora Nijboer, Angela M. Kaindl, Stéphanie Sigaut, Géraldine Favrais, Frank Plaisant, Natacha Teissier, Elodie Gouadon, Alain Lombet, Elie Saliba, Graham L. Collingridge, Mervyn Maze, Ferdinando Nicoletti, Cobi Heijnen, Jean Mantz, Annemieke Kavelaars, Pierre Gressens

Research output: Contribution to journalArticlepeer-review

Abstract

Objective The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. Methods We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1β-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation. Results We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. Interpretation Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders. Ann Neurol 2013;73:667-678

Original languageEnglish
Pages (from-to)667-678
Number of pages12
JournalAnnals of Neurology
Volume73
Issue number5
DOIs
Publication statusPublished - May 2013

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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