Microglia and Glutamate

Abstract

Accumulation of activated microglia around degenerative neurons is a common pathological observation in a variety of neurologic disorders. Activated microglia release a large amount of glutamate that induces neurodegeneration in numerous neurologic diseases such as ischemia, inflammation, epilepsy, and neurodegenerative diseases. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for activated microglia-mediated neurodegenerative diseases, clinical trials have been failed because of adverse effects presumably stemming from disrupted physiological glutamate signaling and suppressed neuroprotective microglial functions. Recent studies revealed that activated microglia specifically produce glutamate using glutaminase and release glutamate via cell-surface gap junction hemichannels. Blockade of microglial hemichannel successfully suppressed disease progression in animal models of brain ischemia, chronic neuropathic pain, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Therefore, hemichannel blockers may offer a promising therapy for various neurologic disorders without causing the above-mentioned adverse effects.