{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T17:04:24Z","timestamp":1778259864369,"version":"3.51.4"},"reference-count":37,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T00:00:00Z","timestamp":1691971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002081","name":"Irish Research Council","doi-asserted-by":"publisher","award":["GOIPD\/2020\/806"],"award-info":[{"award-number":["GOIPD\/2020\/806"]}],"id":[{"id":"10.13039\/501100002081","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["16\/RC\/3948"],"award-info":[{"award-number":["16\/RC\/3948"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["17\/CDA\/4708"],"award-info":[{"award-number":["17\/CDA\/4708"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2023,10]]},"abstract":"Abstract<\/jats:title>Objective<\/jats:title>Posttranscriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large\u2010scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element\u2010binding protein CPEB4 was found to drive epilepsy\u2010induced poly(A) tail changes, and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood.<\/jats:p><\/jats:sec>Methods<\/jats:title>Status epilepticus was induced in wild\u2010type and CPEB4\u2010deficient male mice via an intra\u2010amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via chromatin immunoprecipitation assay and melatonin levels via high\u2010performance liquid chromatography in plasma.<\/jats:p><\/jats:sec>Results<\/jats:title>Here, we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4<\/jats:italic> mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4\u2010dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock<\/jats:italic> transcripts displayed a longer poly(A) tail length in the hippocampus of mice post\u2010status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post\u2010status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug\u2010resistant temporal lobe epilepsy. Furthermore, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4\u2010deficient compared to wild\u2010type mice. Last, CPEB4\u2010deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day.<\/jats:p><\/jats:sec>Significance<\/jats:title>Our results reveal a new positive transcriptional\u2013translational feedback loop involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep\u2013wake cycle during epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17736","type":"journal-article","created":{"date-parts":[[2023,8,6]],"date-time":"2023-08-06T10:29:11Z","timestamp":1691317751000},"page":"2827-2840","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["CPEB4\u2013CLOCK crosstalk during temporal lobe epilepsy"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1404-5803","authenticated-orcid":false,"given":"Laura","family":"de Diego\u2010Garcia","sequence":"first","affiliation":[{"name":"Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland RCSI University of Medicine and Health Sciences Dublin Ireland"},{"name":"Ocupharm Group Research, Faculty of Optics and Optometry University Complutense of Madrid Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary P.","family":"Brennan","sequence":"additional","affiliation":[{"name":"School of Biomolecular and Biomedical Science UCD Conway Institute, University College Dublin Dublin Ireland"},{"name":"FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases Royal College of Surgeons in Ireland, University of Medicine and Health Sciences Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa","family":"Auer","sequence":"additional","affiliation":[{"name":"School of Biomolecular 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Diseases Instituto de Salud Carlos III Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leticia","family":"Villalba\u2010Benito","sequence":"additional","affiliation":[{"name":"School of Biomolecular and Biomedical Science UCD Conway Institute, University College Dublin Dublin Ireland"},{"name":"FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases Royal College of Surgeons in Ireland, University of Medicine and Health Sciences Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland RCSI University of Medicine and Health Sciences Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland RCSI University of Medicine and Health Sciences Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelvin","family":"Lau","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland RCSI University of Medicine and Health Sciences Dublin Ireland"},{"name":"FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases Royal College of Surgeons in Ireland, University of Medicine and Health Sciences Dublin 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