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Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using <jats:italic>Iba1<\/jats:italic>\u2010tTA::<jats:italic>DTA<\/jats:italic><jats:sup>tetO\/tetO<\/jats:sup> mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up\u2010regulation of proinflammatory cytokine genes including <jats:italic>Il1b<\/jats:italic>, <jats:italic>Il6<\/jats:italic> and <jats:italic>Tnfa<\/jats:italic>, among which <jats:italic>Tnfa<\/jats:italic> was selectively blocked by minocycline. PLX5622 also suppressed <jats:italic>Tnfa<\/jats:italic> expression. Tumor necrosis factor \u03b1 (TNF\u03b1) signals were restricted in microglia at very early followed by spreading into other cell types. TNF\u03b1 up\u2010regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNF\u03b1 induction. Both inhibition of TNF\u03b1 and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA\u2010induced degeneration of RGCs, suggesting an importance of non\u2010cell\u2010autonomous mechanism in the retinal neuronal excitotoxicity.<\/jats:p>","DOI":"10.1002\/glia.23475","type":"journal-article","created":{"date-parts":[[2018,10,30]],"date-time":"2018-10-30T09:35:00Z","timestamp":1540892100000},"page":"2366-2384","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Microglia mediate non\u2010cell\u2010autonomous cell death of retinal ganglion cells"],"prefix":"10.1002","volume":"66","author":[{"given":"Akiko","family":"Takeda","sequence":"first","affiliation":[{"name":"Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youichi","family":"Shinozaki","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Kashiwagi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Interdisciplinary Graduate School of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Division of Neurobiology and Bioinformatics National Institute for Physiological Sciences (NIPS)  Aichi Japan"},{"name":"Department of Anatomy Jichi Medical University  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Eto","sequence":"additional","affiliation":[{"name":"Division of Homeostatic Development, NIPS  Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8543-4590","authenticated-orcid":false,"given":"Hiroaki","family":"Wake","sequence":"additional","affiliation":[{"name":"Division of Homeostatic Development, NIPS  Aichi Japan"},{"name":"Division of System Neuroscience, Graduate School of Medicine Kobe University  Hyogo Japan"},{"name":"Precursory Research for Embryonic Science and Technology Japan Science and Technology Agency  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Nabekura","sequence":"additional","affiliation":[{"name":"Division of Homeostatic Development, NIPS  Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6184-3106","authenticated-orcid":false,"given":"Schuichi","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep31545"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004170050156"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1820-08.2008"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2147\/OPTH.S19453"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.04.011"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-1337"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22516"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0042-6989(97)00176-4"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1442-9071.2006.01146.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09413"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/neu.480230915"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1472"},{"key":"e_1_2_8_14_1","first-page":"688","article-title":"Evidence for glutamate\u2010mediated excitotoxic mechanisms during photoreceptor degeneration in the rd1 mouse retina","volume":"11","author":"Delyfer M. 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