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Here, we wished to determine the potential of the Parkinson's disease (PD) protein \u03b1\u2010Synuclein (\u03b1S) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate release was robustly increased when microglial cultures were treated with fibrillary aggregates of \u03b1S but not with the native monomeric protein. Promotion of microglial glutamate release by \u03b1S aggregates (\u03b1Sa) required concomitant engagement of TLR2 and P2X7 receptors. Downstream to cell surface receptors, the release process was mediated by activation of a signaling cascade sequentially involving phosphoinositide 3\u2010kinase (PI3K) and NADPH oxidase, a superoxide\u2010producing enzyme. Inhibition of the Xc\u2010 antiporter, a plasma membrane exchange system that imports extracellular <jats:sc>l<\/jats:sc>\u2010cystine and exports intracellular glutamate, prevented the release of glutamate induced by \u03b1Sa, indicating that system Xc\u2010 was the final effector element in the release process downstream to NADPH oxidase activation. Of interest, the stimulation of glutamate release by \u03b1Sa was abrogated by dopamine through an antioxidant effect requiring D<jats:sub>1<\/jats:sub> dopamine receptor activation and PI3K inhibition. Altogether, present data suggest that the activation of microglial cells by \u03b1Sa may possibly result in a toxic build\u2010up of extracellular glutamate contributing to excitotoxic stress in PD. The deficit in dopamine that characterizes this disorder may further aggravate this process in a vicious circle mechanism.<\/jats:p>","DOI":"10.1002\/glia.23472","type":"journal-article","created":{"date-parts":[[2018,11,5]],"date-time":"2018-11-05T10:35:28Z","timestamp":1541414128000},"page":"2353-2365","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Microglial glutamate release evoked by \u03b1\u2010synuclein aggregates is prevented by dopamine"],"prefix":"10.1002","volume":"66","author":[{"given":"Mauricio","family":"dos\u2010Santos\u2010Pereira","sequence":"first","affiliation":[{"name":"Institut du Cerveau et de la Moelle \u00e9pini\u00e8re (ICM), Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9  Paris F\u201075013 France"},{"name":"Faculdade de Medicina de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo  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