{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:52:03Z","timestamp":1787806323638,"version":"build-2784847793"},"reference-count":87,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T00:00:00Z","timestamp":1720396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Fragile X syndrome (FXS), the most frequent monogenic form of intellectual disability, is caused by transcriptional silencing of the <jats:italic>FMR1<\/jats:italic> gene that could render neuronal hyperexcitability. Here we show that pyramidal cells (PCs) in the dorsal CA1 region of the hippocampus elicited a larger action potential (AP) number in response to suprathreshold stimulation in juvenile <jats:italic>Fmr1<\/jats:italic> knockout (KO) than wild\u2010type (WT) mice. Because Kv7\/M channels modulate CA1 PC excitability in rats, we investigated if their dysfunction produces neuronal hyperexcitability in <jats:italic>Fmr1<\/jats:italic> KO mice. Immunohistochemical and western blot analyses showed no differences in the expression of Kv7.2 and Kv7.3 channel subunits between genotypes; however, the current mediated by Kv7\/M channels was reduced in <jats:italic>Fmr1<\/jats:italic> KO mice. In both genotypes, bath application of XE991 (10\u00a0\u03bcM), a blocker of Kv7\/M channels: produced an increased AP number, produced an increased input resistance, produced a decreased AP voltage threshold and shaped AP medium afterhyperpolarization by increasing mean velocities. Retigabine (10\u00a0\u03bcM), an opener of Kv7\/M channels, produced opposite effects to XE991. Both XE991 and retigabine abolished differences in all these parameters found in control conditions between genotypes. Furthermore, a low concentration of retigabine (2.5\u00a0\u03bcM) normalized CA1 PC excitability of <jats:italic>Fmr1<\/jats:italic> KO mice. Finally, <jats:italic>ex vivo<\/jats:italic> seizure\u2010like events evoked by 4\u2010aminopyiridine (200\u00a0\u03bcM) in the dorsal CA1 region were more frequent in <jats:italic>Fmr1<\/jats:italic> KO mice, and were abolished by retigabine (5\u201310\u00a0\u03bcM). We conclude that CA1 PCs of <jats:italic>Fmr1<\/jats:italic> KO mice exhibit hyperexcitability, caused by Kv7\/M channel dysfunction, and increased epileptiform activity, which were abolished by retigabine.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16194-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Dorsal pyramidal cells of the hippocampal CA1 region of <jats:italic>Fmr1<\/jats:italic> knockout mice exhibit hyperexcitability.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Kv7\/M channel activity, but not expression, is reduced in pyramidal cells of the hippocampal CA1 region of <jats:italic>Fmr1<\/jats:italic> knockout mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Kv7\/M channel dysfunction causes hyperexcitability in pyramidal cells of the hippocampal CA1 region of <jats:italic>Fmr1<\/jats:italic> knockout mice by increasing input resistance, decreasing AP voltage threshold and shaping medium afterhyperpolarization.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A Kv7\/M channel opener normalizes neuronal excitability in pyramidal cells of the hippocampal CA1 region of <jats:italic>Fmr1<\/jats:italic> knockout mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>Ex vivo<\/jats:italic> seizure\u2010like events evoked in the dorsal CA1 region were more frequent in <jats:italic>Fmr1<\/jats:italic> KO mice, and such an epileptiform activity was abolished by a Kv7\/M channel opener depending on drug concentration.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Kv7\/M channels may represent a therapeutic target for treating symptoms associated with hippocampal alterations in fragile X syndrome.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285244","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T17:00:59Z","timestamp":1720458059000},"page":"3769-3791","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Kv7\/M channel dysfunction produces hyperexcitability in hippocampal CA1 pyramidal cells of <i>Fmr1<\/i> knockout mice"],"prefix":"10.1113","volume":"602","author":[{"given":"M. Angeles","family":"Luque","sequence":"first","affiliation":[{"name":"Departamento Fisiolog\u00eda, Facultad de Biolog\u00eda Universidad de Sevilla Sevilla Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Morcuende","sequence":"additional","affiliation":[{"name":"Departamento Fisiolog\u00eda, Facultad de Biolog\u00eda Universidad de Sevilla Sevilla Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4508-4546","authenticated-orcid":false,"given":"Blas","family":"Torres","sequence":"additional","affiliation":[{"name":"Departamento Fisiolog\u00eda, Facultad de Biolog\u00eda Universidad de Sevilla Sevilla Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4311-8792","authenticated-orcid":false,"given":"Luis","family":"Herrero","sequence":"additional","affiliation":[{"name":"Departamento Fisiolog\u00eda, Facultad de Biolog\u00eda Universidad de Sevilla 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