Microglia express functional NMDA receptors: A novel finding and a promise for innovative treatment of excitotoxic and inflammatory brain disease

Inflammation and glutamate-mediated excitotoxicity are major contributors to the pathogenesis of neurodegenerative disorders. In this context, the activation of microglia, the resident macrophages of the central nervous system, plays a pivotal role. Still, the exact mechanisms capable of activating microglia in the excitotoxic context are unknown. Functional NMDA receptors (NMDAR) have so far not been described on microglia and their presence has been thus highly controversial. Here, we demonstrate for the first time that microglial NMDAR exist and are functional in murine and human brains using various sophisticated experimental approaches. NMDAR subunits NR1, NR2A-D and NR3A are present on cultured microglia as demonstrated through RT-PCR, Western blot and/or confocal microscopic imaging of immunohistologically labeled specimen. In developmental and adult mouse and human brain sections, about 1% of microglia were NR1 positive in the cortical white matter. These microglia were more numerous within the developing than in the mature brain and more frequently of the intermediate or amoeboid than of the ramified phenotype. NMDAR activation triggered a change of microglia phenotype, an increase of intracellular Ca2+ concentration and an inward current as demonstrated by time lapse imaging, calcium imaging and electrophysiological analyses, respectively. These NMDA-induced responses could be blocked by the NMDAR inhibitor MK801. NMDAR activation further promoted an increase of oxidative stress, cytokines and chemokines in cultured microglia. Factors secreted into the medium by NMDAR-activated microglia caused neuronal cell death in vitro.

Our novel finding renders microglia physiologic communication partners within the neuronal network and highlights their importance for the evolution of glutamate-triggered neurodegeneration. The existence of microglial NMDAR further offers a link between inflammation and excitotoxicity and establishes a promising target for novel innovative therapeutic interventions in neurodegenerative disorders.