Journal
ANNALS OF NEUROLOGY
Volume 73, Issue 5, Pages 667-678Publisher
WILEY
DOI: 10.1002/ana.23868
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Funding
- Fondation Motrice and National Institute of Health [NS073939, NS074999]
- Inserm
- Universite Paris 7
- APHP (Contrat Hospitalier de Recherche Translationnelle)
- PremUP
- Sixth Framework Program of the European Commission [LSHM-CT-2006-036534/NEOBRAIN]
- Seventh Framework Program of the European Union [HEALTH-F2-2009-241778/NEURO-BID]
- Fondation Roger de Spoelberch
- Fondation Grace de Monaco
- Fondation Leducq
- Fondation pour la Recherche Medicale
- Institut pour la Recherche sur la Moelle epiniere et l'Encephale
- Fondation des Gueules Cassees
- Fondation Areva
- Societe Francaise d'Anesthesie Reanimation
- Fondation ELA (European Leukodystrophies Association)
- UK Medical Research Council
- WCU program through the KOSEF (Korea Science and Engineering Foundation)
- MEST (Korean Ministry of Education, Science and Technology) [R31-10089]
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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)-1-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1 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.
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