期刊
ANNALS OF NEUROLOGY
卷 72, 期 4, 页码 536-549出版社
WILEY
DOI: 10.1002/ana.23626
关键词
-
资金
- Inserm
- Universite Paris 7
- Leducq Foundation
- European Commission [LSHM-CT-2006-036534/neobrain]
- PremUP
- Institut pour la Recherche sur la Moelle epiniere et l'Encephale
- Fondation des Gueules Cassees
- Fondation Motrice
- ELA Foundation
- Fondation Grace de Monaco
- Sonnenfeld Stiftung
- German Research Foundation [SFB665]
- Berliner Krebsgesellschaft e.V.
- Societe Francaise d'Anesthesie Reanimation, MRC (UK)
- APHP (Contrat d'Interface)
- EU
- NIH
- Medical Research Council [G0601813, G0601841B] Funding Source: researchfish
- MRC [G0601813] Funding Source: UKRI
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;72:536549
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据