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However, the precise molecular mechanisms underlying its action remain elusive. Using RNA-sequencing analysis, we searched for novel molecular target(s) that contribute to the prophylactic effects of (\n                    <jats:italic>R<\/jats:italic>\n                    )-ketamine, a more potent enantiomer of (\n                    <jats:italic>R,S<\/jats:italic>\n                    )-ketamine in chronic restraint stress (CRS) model. Pretreatment with (\n                    <jats:italic>R<\/jats:italic>\n                    )-ketamine (10\u2009mg\/kg, 1 day before CRS) significantly ameliorated body weight loss, increased immobility time of forced swimming test, and decreased sucrose preference of sucrose preference test in CRS-exposed mice. RNA-sequencing analysis of prefrontal cortex (PFC) revealed that several miRNAs such as miR-132-5p might contribute to sustained prophylactic effects of (\n                    <jats:italic>R<\/jats:italic>\n                    )-ketamine. Methyl CpG binding protein 2 (MeCP2) is known to regulate brain-derived neurotrophic factor (BDNF) expression. Quantitative RT-PCR confirmed that (\n                    <jats:italic>R<\/jats:italic>\n                    )-ketamine significantly attenuated altered expression of\n                    <jats:italic>miR-132-5p<\/jats:italic>\n                    and its regulated genes (\n                    <jats:italic>Bdnf, Mecp2, Tgfb1, Tgfbr2<\/jats:italic>\n                    ) in the PFC of CRS-exposed mice. Furthermore, (\n                    <jats:italic>R<\/jats:italic>\n                    )-ketamine significantly attenuated altered expression of BDNF, MeCP2, TGF-\u03b21 (transforming growth factor \u03b21), and synaptic proteins (PSD-95, and GluA1) in the PFC of CRS-exposed mice. Administration of agomiR-132-5p decreased the expression of\n                    <jats:italic>Bdnf<\/jats:italic>\n                    and\n                    <jats:italic>Tgfb1<\/jats:italic>\n                    in the PFC, resulting in depression-like behaviors. In contrast, administration of antagomiR-132-5p blocked the increased expression of\n                    <jats:italic>miR-132-5p<\/jats:italic>\n                    and decreased expression of\n                    <jats:italic>Bdnf<\/jats:italic>\n                    in the PFC of CRS-exposed mice, resulting in antidepressant-like effects. In conclusion, our data show a novel role of miR-132-5p in the PFC underlying depression-like phenotypes in CRS model and the sustained prophylactic effects of (\n                    <jats:italic>R<\/jats:italic>\n                    )-ketamine.\n                  <\/jats:p>","DOI":"10.1038\/s41398-022-02192-6","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T06:04:44Z","timestamp":1664345084000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["A key role of miR-132-5p in the prefrontal cortex for persistent prophylactic actions of (R)-ketamine in mice"],"prefix":"10.1038","volume":"12","author":[{"given":"Li","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijia","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajing","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youge","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiayun","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Fujita","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":[[2022,9,28]]},"reference":[{"key":"2192_CR1","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/S0006-3223(99)00230-9","volume":"47","author":"RM Berman","year":"2000","unstructured":"Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. 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Hashimoto is the inventor of filed patent applications on \u201cThe use of R-Ketamine in the treatment of psychiatric diseases\u201d, \u201c(S)-norketamine and salt thereof as pharmaceutical\u201d, \u201cR-Ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder\u201d, \u201cPreventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases\u201d, and \u201cR-Ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder\u201d by the Chiba University. Dr. K. Hashimoto has also received speakers\u2019 honoraria, consultant fee, or research support from Abbott, Meiji Seika Pharma, Seikagaku Corporation, Sumitomo Pharma, Taisho, Otsuka, Murakami Farm and Perception Neuroscience. Other authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"417"}}