title: Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain.
abstract: OBJECTIVE
  Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their activation in the latter context are poorly understood, particularly the involvement of N-methyl-D-aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation.
  
  
  RESULTS
  We demonstrate that microglia express NMDARs in the murine and human central nervous system and that these receptors are functional in vitro. We show that NMDAR stimulation triggers microglia activation in vitro and secretion of factors that induce cell death of cortical neurons. These damaged neurons are further shown to activate microglial NMDARs and trigger a release of neurotoxic factors from microglia in vitro, indicating that microglia can signal back to neurons and possibly induce, aggravate, and/or maintain neurologic disease. Neuronal cell death was significantly reduced through pharmacological inhibition or genetically induced loss of function of the microglial NMDARs. We generated Nr1 LoxP(+/+) LysM Cre(+/-) mice lacking the NMDAR subunit NR1 in cells of the myeloid lineage. In this model, we further demonstrate that a loss of function of the essential NMDAR subunit NR1 protects from excitotoxic neuronal cell death in vivo and from traumatic brain injury.
  
  
  CONCLUSIONS
  Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain.
authors.affiliation: French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France. angela.kaindl@charite.de
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kaindl
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.forename: Stéphane
authors.initials: S
authors.lastname: Peineau
authors.forename: Elodie
authors.initials: E
authors.lastname: Gouadon
authors.forename: Vibol
authors.initials: V
authors.lastname: Chhor
authors.forename: Gauthier
authors.initials: G
authors.lastname: Loron
authors.forename: Tifenn
authors.initials: T
authors.lastname: Le Charpentier
authors.forename: Julien
authors.initials: J
authors.lastname: Josserand
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: Alain
authors.initials: A
authors.lastname: Lombet
authors.forename: Lina
authors.initials: L
authors.lastname: Issa
authors.forename: Frédérique
authors.initials: F
authors.lastname: Rene
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Catherine
authors.initials: C
authors.lastname: Verney
authors.forename: Jean
authors.initials: J
authors.lastname: Mantz
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D006801:Humans; D007051:Ibotenic Acid / Q000633:toxicity; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D018613:Microscopy, Confocal; D019579:Neocortex / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D020521:Stroke / Q000473:pathology
chemical_list: D017077:Culture Media, Conditioned; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D007051:Ibotenic Acid; D002118:Calcium