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Vezatin has been reported to be a synaptic regulatory protein involved in regulating neuronal synaptic transmission (NST). However, the role of vezatin in epilepsy remains unknown. Therefore, the aims of this study are to investigate the underlying roles of vezatin in epilepsy. In this study, vezatin expression was increased in hippocampal tissues from pilocarpine (PILO)-induced epileptic mice and a Mg<jats:sup>2+<\/jats:sup>-free medium-induced in vitro seizure-like model. Vezatin knockdown suppressed seizure activity in PILO-induced epileptic mice. Mechanistically, vezatin knockdown suppressed AMPAR-mediated synaptic events in epileptic mice and downregulated the surface expression of the AMPAR GluA1 subunit (GluA1). Interestingly, vezatin knockdown decreased the phosphorylation of GluA1 at serine 845 and reduced protein kinase A (PKA) phosphorylation; when PKA phosphorylation was suppressed by H-89 (a selective inhibitor of PKA phosphorylation) in vitro, the effects of vezatin knockdown on reducing the phosphorylation of GluA1 at serine 845 and the surface expression of GluA1 were blocked. Finally, we investigated the pattern of vezatin in brain tissues from patients with temporal lobe epilepsy (TLE), and we found that vezatin expression was also increased in patients with TLE. In summary, the vezatin expression pattern is abnormal in individuals with epilepsy, and vezatin regulates seizure activity by affecting AMPAR-mediated NST and the surface expression of GluA1, which is involved in PKA-mediated phosphorylation of GluA1 at serine 845, indicating that vezatin-mediated regulation of epileptic seizures represents a novel target for epilepsy.<\/jats:p>","DOI":"10.1038\/s41419-021-04233-2","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T23:30:55Z","timestamp":1634081455000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Vezatin regulates seizures by controlling AMPAR-mediated synaptic activity"],"prefix":"10.1038","volume":"12","author":[{"given":"You","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxian","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangmei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6006-5621","authenticated-orcid":false,"given":"Tao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"4233_CR1","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1016\/S0140-6736(14)60456-6","volume":"385","author":"SL Moshe","year":"2015","unstructured":"Moshe SL, Perucca E, Ryvlin P, Tomson T. 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