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Recently, studies demonstrate that antidepressants generating BDNF not only maintain synaptic signal transmission but also repress neuroinflammatory cytokines such as IL-6 and IL-1\u03b2. Therefore, promoting BDNF expression provides a strategy for the treatment of depression. Our recent research has indicated that programmed cell death 4 (Pdcd4) is a new target for antidepressant treatment by facilitating BDNF. Herein, we modified Pdcd4 specific small interfering RNA (siPdcd4) with the rabies virus glycoprotein peptide (RVG\/siPdcd4) which enables it cross the blood-brain barrier (BBB). We found that RVG\/siPdcd4 complex was selectively delivered to neurons and microglia and silenced the expression of Pdcd4, thereby up-regulating the level of BDNF and down-regulating IL-6 and IL-1\u03b2 expression. More importantly, RVG\/siPdcd4 injection attenuated synaptic plasticity impairment and protected mice from CRS-induced depressive behavior. These findings suggest that RVG\/siPdcd4 complex is a potential therapeutic medicine for depression.<\/jats:p>","DOI":"10.1038\/s41419-021-04361-9","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T19:03:04Z","timestamp":1636743784000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The brain targeted delivery of programmed cell death 4 specific siRNA protects mice from CRS-induced depressive behavior"],"prefix":"10.1038","volume":"12","author":[{"given":"Yufeng","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faliang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1935-4477","authenticated-orcid":false,"given":"Yuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8977-1148","authenticated-orcid":false,"given":"Lining","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"4361_CR1","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","volume":"392","author":"GBD Disease","year":"2018","unstructured":"Disease GBD, Injury I, Prevalence C. 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