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SAPAP3, a cytoskeletal protein expressed at high levels in the postsynaptic density (PSD) of excitatory synapses, has been well studied in the striatum, but the role of SAPAP3 in epilepsy remains elusive. In this study, we sought to investigate the molecular, cellular, electrophysiological and behavioral consequences of SAPAP3 perturbations in the mouse hippocampus. We identified a significant increase in the SAPAP3 levels in patients with temporal lobe epilepsy (TLE) and in mouse models of epilepsy. In addition, behavioral studies showed that the downregulation of SAPAP3 by shRNA decreased the seizure severity and that the overexpression of SAPAP3 by recombinant SAPAP3 yielded the opposite effect. Moreover, SAPAP3 affected action potentials (APs), miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents in the CA1 region, which indicated that SAPAP3 plays an important role in excitatory synaptic transmission. Additionally, the levels of the GluN2A protein, which is involved in synaptic function, were perturbed in the hippocampal PSD, and this perturbation was accompanied by ultrastructural morphological changes. These results revealed a previously unknown function of SAPAP3 in epileptogenesis and showed that SAPAP3 may represent a novel target for the treatment of epilepsy.<\/jats:p>","DOI":"10.1038\/s41419-022-04876-9","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T14:04:11Z","timestamp":1651759451000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities"],"prefix":"10.1038","volume":"13","author":[{"given":"Yanke","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixue","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanlin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyan","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"L\u00fc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8118-1573","authenticated-orcid":false,"given":"Wei","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1494-0223","authenticated-orcid":false,"given":"Xuefeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1552-8919","authenticated-orcid":false,"given":"Xin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"4876_CR1","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1016\/S0140-6736(06)68477-8","volume":"367","author":"JS Duncan","year":"2006","unstructured":"Duncan JS, Sander JW, Sisodiya SM, Walker MC. 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All surgical procedures with mice were performed under anesthesia, and every effort was made to minimize their suffering. Informed consent was obtained from the patients involved in this experiment. All protocols related to human research were in accordance with the guidelines established by the Committee on Human Research at the First Affiliated Hospital of Chongqing Medical University and the National Institutes of Health.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"437"}}