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Here, we found that inhibition of Receptor-Interacting Serine\/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2\/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.<\/jats:p>","DOI":"10.1073\/pnas.2320383121","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T13:30:15Z","timestamp":1706621415000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":15,"title":["RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT"],"prefix":"10.1073","volume":"121","author":[{"given":"Ze","family":"Cao","sequence":"first","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Min","sequence":"additional","affiliation":[{"name":"Interdisciplinary 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