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Despite the cellular and molecular facilitations on neural protection, the molecular mechanisms of spontaneous recovery have not been fully understood. Ca<jats:sup>2+<\/jats:sup>\u2010dependent activator protein for secretion 1 (CAPS1), a member of CAPS family, plays a major role in synaptic transmission and synaptic effectiveness by regulating vesicle exocytosis. Here, the molecular mechanism of CAPS1 in spontaneous recovery after ischemic stroke was studied. In this study, transient left middle cerebral artery occlusion (MCAO) was used as the ischemic stroke model. The whole brain magnetic resonance imaging (MRI) and neurological score analysis showed decreased infarct volume and neurological scores at 7\u2009days as compared with 1\u00a0day after MCAO, suggesting the spontaneous recovery. Elisa and Western blot analysis showed elevated BDNF and CAPS1 expression levels in bilateral hippocampus at both 1\u00a0day and 3\u2009days after MCAO. Then, inhibition of CAPS1 by adeno\u2010associated virus (AAV) microinjection in the hippocampus attenuated the spontaneous recovery of both motor and memory impairment induced by MCAO. In addition, elevated p\u2010TrkB levels were detected after MCAO, which were reduced by CAPS1\u2010AAV microinjection, indicating that CAPS1 could induce BDNF secretion after ischemic stroke. Moreover, we found elevated combination of CAPS1 with dense core vesicles (DCV) in the hippocampus at both 1\u00a0day and 3\u2009days after MCAO, which could also be inhibited by CAPS1\u2010AAV microinjection, indicating the potential mechanism of CAPS1 in regulating BDNF release after MCAO. Finally, we found that CAPS1\/BDNF signaling could influence the neurogenesis in the hippocampus after MCAO. In conclusion, CAPS1 regulates neurogenesis by up\u2010regulating BDNF release in the hippocampus, which finally facilitate spontaneous recovery after ischemic stroke.<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\/jnc15808-fig-0011-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15808","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T09:43:57Z","timestamp":1678787037000},"page":"587-602","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ca<sup>2+<\/sup>\u2010dependent activator protein for secretion 1 promotes spontaneous recovery in ischemic stroke by regulating<scp>BDNF<\/scp>secretion"],"prefix":"10.1111","volume":"165","author":[{"given":"DianWei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Stroke Center Central Hospital Affiliated to Shandong First Medical University Jinan People's Republic of China"},{"name":"Department of Stroke Center Jinan Central Hospital, Cheeloo College of Medicine, Shandong University Jinan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Research Center of Translational Medicine Central Hospital Affiliated to Shandong First Medical University Jinan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University Jinan People's Republic of 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