TY - JOUR
T1 - Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain
AU - Kaindl, Angela M.
AU - Degos, Vincent
AU - Peineau, Stéphane
AU - Gouadon, Elodie
AU - Chhor, Vibol
AU - Loron, Gauthier
AU - Le Charpentier, Tifenn
AU - Josserand, Julien
AU - Ali, Carine
AU - Vivien, Denis
AU - Collingridge, Graham L.
AU - Lombet, Alain
AU - Issa, Lina
AU - Rene, Frédérique
AU - Loeffler, Jean Philippe
AU - Kavelaars, Annemieke
AU - Verney, Catherine
AU - Mantz, Jean
AU - Gressens, Pierre
PY - 2012/10
Y1 - 2012/10
N2 - 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. Methods and 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. Interpretation: 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. ANN NEUROL 2012;72:536-549
AB - 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. Methods and 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. Interpretation: 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. ANN NEUROL 2012;72:536-549
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U2 - 10.1002/ana.23626
DO - 10.1002/ana.23626
M3 - Article
C2 - 23109148
AN - SCOPUS:84868094724
SN - 0364-5134
VL - 72
SP - 536
EP - 549
JO - Annals of Neurology
JF - Annals of Neurology
IS - 4
ER -