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Previously, we reported that microglia synthesized and secreted bioactive mediators with neurotoxic potential into the cultured supernatants in response to JEV infection. In this study, we found that the supernatants of JEV\u2010infected microglia caused MK801\u2010inhibitable neuronal damage in cultured neurons, indicating a potential excitotoxic mechanism. Infection with JEV was found to elicit the extracellular glutamate accumulation from microglia but not from neuron and astrocyte cultures. The glutaminase inhibitor 6\u2010diazo\u20105\u2010oxo\u2010<jats:sc>L<\/jats:sc>\u2010norleucine, cystine\/glutamate antiporter inhibitor \u03b1\u2010aminoadipic acid, and the gap junction inhibitor carbenoxolone reduced JEV infection\u2010induced microglial glutamate release and neurotoxicity. We further demonstrated that tumor necrosis factor\u2010alpha (TNF\u2010\u03b1) was a key cytokine which stimulated extensive microglial glutamate release by up\u2010regulating glutaminase expression via signals involving protein kinase C, cAMP responsive element\u2010binding protein, and CAAT\u2010enhancer\u2010binding protein\u2010beta. Although the elevated expression of excitatory amino acid transporter 1 and 2 was observed in JEV\u2010infected cells, the glutamate uptake activity was significantly inhibited by TNF\u2010\u03b1. The JEV infection\u2010induced alterations, such as the extracellular glutamate release and glutamate\u2010mediated excitoneurotoxicity, also occurred in neuron\/glia cultures. Our findings support a potential link between neuroinflammation and the development of excitotoxic neuronal injury in Japanese encephalitis. The link between neuroinflammation and excitotoxic death may involve a mechanism in which TNF\u2010\u03b1 released by microglia plays a facilitory role in glutamate excitoneurotoxicity via up\u2010regulation of glutamate synthesis and down\u2010regulation of glutamate uptake. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/glia.22282","type":"journal-article","created":{"date-parts":[[2011,12,6]],"date-time":"2011-12-06T01:02:49Z","timestamp":1323133369000},"page":"487-501","source":"Crossref","is-referenced-by-count":105,"title":["Glutamate released by Japanese encephalitis virus\u2010infected microglia involves TNF\u2010\u03b1 signaling and contributes to neuronal 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