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Using RNA-sequencing analysis, we identified novel molecular targets that contribute to the different antidepressant effects of the two enantiomers. Either (<jats:italic>R<\/jats:italic>)-ketamine (10\u2009mg\/kg) or (<jats:italic>S<\/jats:italic>)-ketamine (10\u2009mg\/kg) was administered to susceptible mice after chronic social defeat stress (CSDS). RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent GSEA (gene set enrichment analysis) revealed that transforming growth factor (TGF)-\u03b2 signaling might contribute to the different antidepressant effects of the two enantiomers. (<jats:italic>R<\/jats:italic>)-ketamine, but not (<jats:italic>S<\/jats:italic>)-ketamine, ameliorated the reduced expressions of <jats:italic>Tgfb1<\/jats:italic> and its receptors (<jats:italic>Tgfbr1<\/jats:italic> and <jats:italic>Tgfbr2<\/jats:italic>) in the PFC and hippocampus of CSDS susceptible mice. Either pharmacological inhibitors (i.e., RepSox and SB431542) or neutralizing antibody of TGF-\u03b21 blocked the antidepressant effects of (<jats:italic>R<\/jats:italic>)-ketamine in CSDS susceptible mice. Moreover, depletion of microglia by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant effects of (<jats:italic>R<\/jats:italic>)-ketamine in CSDS susceptible mice. Similar to (<jats:italic>R<\/jats:italic>)-ketamine, the recombinant TGF-\u03b21 elicited rapid and long-lasting antidepressant effects in animal models of depression. Our data implicate a novel microglial TGF-\u03b21-dependent mechanism underlying the antidepressant effects of (<jats:italic>R<\/jats:italic>)-ketamine in rodents with depression-like phenotype. Moreover, TGF-\u03b21 and its receptor agonists would likely constitute a novel rapid-acting and sustained antidepressant in humans.<\/jats:p>","DOI":"10.1038\/s41398-020-0733-x","type":"journal-article","created":{"date-parts":[[2020,2,17]],"date-time":"2020-02-17T15:06:30Z","timestamp":1581951990000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":113,"title":["Essential role of microglial transforming growth factor-\u03b21 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-\u03b21"],"prefix":"10.1038","volume":"10","author":[{"given":"Kai","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijia","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akemi","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youge","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyu","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7313-4067","authenticated-orcid":false,"given":"Yunfei","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamaki","family":"Ishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiko","family":"Shirayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Hatano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2511-0057","authenticated-orcid":false,"given":"Kenji F.","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8892-0439","authenticated-orcid":false,"given":"Kenji","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,27]]},"reference":[{"key":"733_CR1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0014-2999(90)90204-J","volume":"185","author":"R Trullas","year":"1990","unstructured":"Trullas, R. & Skolnick, P. 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