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We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble \u03b2-amyloid oligomers (A\u03b2Os), primarily via restoring the A\u03b2Os-impaired Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload induced by A\u03b2Os. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03592-6","type":"journal-article","created":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T10:59:12Z","timestamp":1775905152000},"page":"5031-5047","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer\u2019s disease models"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3202-2402","authenticated-orcid":false,"given":"Jiaxing","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2326-4167","authenticated-orcid":false,"given":"Zhengjun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Yong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyi","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9422-2450","authenticated-orcid":false,"given":"Yuyang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Rager-Aguiar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay K.","family":"Boda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7479-4005","authenticated-orcid":false,"given":"Tyler C.","family":"Ortyl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7006-6951","authenticated-orcid":false,"given":"Ilya","family":"Bezprozvanny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Ming","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-0975","authenticated-orcid":false,"given":"Jianyang","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongzhi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5144-3600","authenticated-orcid":false,"given":"Francesca-Fang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,11]]},"reference":[{"key":"3592_CR1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe DJ, Hardy J. 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