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In AS mice, a dysregulation of Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase II alpha (CaMKII\u03b1) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross\u2010breeding experiments. Selective ligands that specifically stabilize the CaMKII\u03b1 central association (hub) domain and affect different conformational states in vitro are now available. Two of these ligands, 3\u2010hydroxycyclopent\u20101\u2010enecarboxylic acid (HOCPCA) and (<jats:italic>E<\/jats:italic>)\u20102\u2010(5\u2010hydroxy\u20102\u2010phenyl\u20105,7,8,9\u2010tetrahydro\u20106<jats:italic>H<\/jats:italic>\u2010benzo[7]annulen\u20106\u2010ylidene)acetic acid (Ph\u2010HTBA), confer neuroprotection after ischemic stroke in mice where CaMKII\u03b1 is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKII\u03b1 hub ligands presents a viable approach to alleviate AS symptoms. We performed an in vivo functional evaluation of AS mice treated for a total of 14\u2009days with either HOCPCA or Ph\u2010HTBA (7\u00a0days pre\u2010treatment and 7\u00a0days of behavioural assessment). Both compounds were well\u2010tolerated but unable to revert robust phenotypes of motor performance, anxiety, repetitive behaviour or seizures in AS mice. Biochemical experiments subsequently assessed CaMKII\u03b1 autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKII\u03b1 via the selective hub ligands used here is not a viable treatment strategy in AS.<\/jats:p>","DOI":"10.1111\/bcpt.14112","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T04:05:57Z","timestamp":1734062757000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CaMKII\u03b1 hub ligands are unable to reverse known phenotypes in Angelman syndrome mice"],"prefix":"10.1111","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3017-0962","authenticated-orcid":false,"given":"Stine J.","family":"Gauger","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1947-9125","authenticated-orcid":false,"given":"Maria E. 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