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Thus, breaking this vicious cycle by suppressing neuronal hyperactivity may represent a logical approach to stopping AD progression. In support of this, we have recently shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevented neuronal hyperactivity, memory impairment, dendritic spine loss, and neuronal cell death in a rapid, early onset AD mouse model (5xFAD). Here, we assessed the impact of limiting RyR2 open time on AD\u2010related deficits in a relatively late occurring, slow developing AD mouse model (3xTG\u2010AD) that bears more resemblance (compared to 5xFAD) to that of human AD. Using behavioral tests, long\u2010term potentiation recordings, and Golgi and Nissl staining, we found that the RyR2\u2010E4872Q mutation, which markedly shortens the open duration of the RyR2 channel, prevented learning and memory impairment, defective long\u2010term potentiation, dendritic spine loss, and neuronal cell death in the 3xTG\u2010AD mice. Furthermore, pharmacologically shortening the RyR2 open time with R\u2010carvedilol rescued these AD\u2010related deficits in 3xTG mice. Therefore, limiting RyR2 open time may offer a promising, neuronal hyperactivity\u2010targeted anti\u2010AD strategy.<\/jats:p>","DOI":"10.1002\/jnr.24936","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T14:35:43Z","timestamp":1628174143000},"page":"2906-2921","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Limiting RyR2 open time prevents Alzheimer's disease\u2010related deficits in the 3xTG\u2010AD mouse model"],"prefix":"10.1002","volume":"99","author":[{"given":"Yajing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology Cumming School of Medicine Libin Cardiovascular Institute University of Calgary Calgary AB Canada"},{"name":"Department of Pharmacology Shenyang Pharmaceutical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4602-7159","authenticated-orcid":false,"given":"Jinjing","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Cumming School of Medicine Libin Cardiovascular Institute University of Calgary Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenpeng","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Cumming School of Medicine Libin Cardiovascular Institute University of Calgary Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Cumming School of Medicine Libin Cardiovascular Institute University of Calgary Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Cumming School of Medicine Libin Cardiovascular Institute University of Calgary Calgary AB Canada"},{"name":"Medical School Kunming University of Science and Technology Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Cumming School of Medicine Libin Cardiovascular Institute University of Calgary Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Paul","family":"Estillore","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Cumming School of Medicine Libin Cardiovascular Institute University of Calgary Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Back","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Calgary Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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