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Unfortunately, the currently available antidepressants are not effective in a significant percentage of patients. Therefore, the underlying mechanisms of depression must be explored at the molecular level to discover new candidate molecular targets for depression treatment. Behavioural and molecular depression\u2010like endophenotypes have been observed in cyclic <jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content> response element\u2010binding protein\u2010regulated transcription coactivator 1 (<jats:italic>Crtc1<\/jats:italic>) knockout mice; however, the underlying mechanism for these endophenotypes remains unclear. This work investigated the role of hippocampal CREB\u2010regulated transcription coactivator 1 (<jats:styled-content style=\"fixed-case\">CRTC<\/jats:styled-content>1) in depression using a recombinant adeno\u2010associated virus (<jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>) system to alter <jats:italic>Crtc1<\/jats:italic> gene expression and explore its potential mechanism. We found that sh<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010mediated <jats:italic>Crtc1<\/jats:italic> gene knockdown (<jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>\u2010sh<jats:styled-content style=\"fixed-case\">CRTC<\/jats:styled-content>1) in the dentate gyrus regions of the ventral hippocampus directly resulted in depression\u2010like behaviours and down\u2010regulation of\u00a0brain\u2010derived neurotrophic factor and neuropeptide <jats:styled-content style=\"fixed-case\">VGF<\/jats:styled-content> levels. A widely used depression model induced by lipopolysaccharide administration (0.5\u00a0mg\/kg, i.p.) was applied in our study and was validated by increased immobility time in the tail\u2010suspension and forced swim tests and decreased sucrose consumption in the sucrose preference test. Importantly, <jats:styled-content style=\"fixed-case\">CRTC<\/jats:styled-content>1 over\u2010expression mediated by <jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">CRTC<\/jats:styled-content>1 in the ventral dentate gyrus regions prevented lipopolysaccharide\u2010induced depressive\u2010like behaviours, the down\u2010regulation of brain\u2010derived neurotrophic factor and <jats:styled-content style=\"fixed-case\">VGF<\/jats:styled-content>, and the accumulation of pro\u2010inflammatory cytokines such as interleukin\u20106, interleukin 1\u2010\u03b2 and tumour necrosis factor \u03b1 in mice. Together, our findings indicate that <jats:styled-content style=\"fixed-case\">CRTC<\/jats:styled-content>1 is a key factor in depression\u2010like behaviour and provide an important reference for finding a novel drug target in the neuroinflammatory and neurotrophic pathways for curing depressive disorders.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14670-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Cover Image for this issue: doi: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1111\/jnc.14500\">10.1111\/jnc.14500<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14670","type":"journal-article","created":{"date-parts":[[2019,1,30]],"date-time":"2019-01-30T11:10:55Z","timestamp":1548846655000},"page":"111-125","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Adeno\u2010associated virus\u2010mediated over\u2010expression of CREB\u2010regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide\u2010induced depression\u2010like behaviour in mice"],"prefix":"10.1111","volume":"149","author":[{"given":"Saiqi","family":"Ni","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Pathophysiology Ningbo University Ningbo, Zhejiang PR China"},{"name":"Department of Physiology and Pharmacology Ningbo University School of Medicine Ningbo, Zhejiang PR China"},{"name":"Ningbo Key Laboratory of Behavioural 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