{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T03:16:24Z","timestamp":1771643784925,"version":"3.50.1"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"the World Premier International Research Center Initiative (WPI) from JSPS, AMED","doi-asserted-by":"publisher","award":["JP21zf0127005"],"award-info":[{"award-number":["JP21zf0127005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"the World Premier International Research Center Initiative (WPI) from JSPS, AMED","doi-asserted-by":"publisher","award":["20K06738"],"award-info":[{"award-number":["20K06738"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"the World Premier International Research Center Initiative (WPI) from JSPS, AMED","doi-asserted-by":"publisher","award":["23K05614"],"award-info":[{"award-number":["23K05614"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["JP21zf0127005"],"award-info":[{"award-number":["JP21zf0127005"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["20K06738"],"award-info":[{"award-number":["20K06738"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["23K05614"],"award-info":[{"award-number":["23K05614"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is an X-linked rare neurodevelopmental disorder associated with severe sleep disturbances. However, little is known about the mechanisms underlying sleep disturbances in CDD patients. Here, we employed the electroencephalogram (EEG) recording to characterize sleep\u2013wake behaviors and EEG activity in male CDKL5-deficient mice. We found that young adult and middle-aged Cdkl5 knockout (KO) mice recapitulated sleep phenotypes in patients with CDD, including difficulties in initiating and maintaining sleep, reduction in total sleep time, and frequent night awakenings. Cdkl5 KO mice exhibited pre-sleep arousal, but normal circadian rhythm and homeostatic sleep response. Conditional knockout (cKO) of Cdkl5 in glutamatergic neurons resulted in reduced sleep time and difficulty in sleep maintenance. Further, the rate of age-associated decline in sleep and EEG activity in Cdkl5 KO mice was comparable to that of wild-type littermates. Together, these results confirm a causative role for CDKL5 deficiency in sleep disturbances observed in CDD patients and establish an animal model for translational research of sleep treatment in CDD. Moreover, our results provide valuable information for developing therapeutic strategies and identifying sleep and EEG parameters as potential biomarkers for facilitating preclinical and clinical trials in CDD.<\/jats:p>","DOI":"10.3390\/ijms26083754","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T10:04:56Z","timestamp":1744797896000},"page":"3754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cdkl5 Knockout Mice Recapitulate Sleep Phenotypes of CDKL5 Deficient Disorder"],"prefix":"10.3390","volume":"26","author":[{"given":"Liqin","family":"Cao","sequence":"first","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"},{"name":"Deafness Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Lou","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"},{"name":"HIT Center for Life Sciences (HCLS), School of Life Sciences and Technology, Harbin Institute of Technology, Harbin 150001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"},{"name":"HIT Center for Life Sciences (HCLS), School of Life Sciences and Technology, Harbin Institute of Technology, Harbin 150001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Staci J.","family":"Kim","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"},{"name":"Department of Brain and Cognitive Sciences, Korea Advanced Institute of Science & Technology, Daejeon 34141, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaspar","family":"Vogt","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arisa","family":"Hirano","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teruyuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Tokyo Children Rehabilitation Hospital, Tokyo 208-0011, Japan"},{"name":"Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiaki","family":"Kikkawa","sequence":"additional","affiliation":[{"name":"Deafness Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghua","family":"Liu","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan"},{"name":"National Institute of Biological Sciences (NIBS), Beijing 102206, China"},{"name":"Tsinghua Institute of Multidisciplinary Biomedical Research (TIMBR), Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"ref_1","first-page":"137","article-title":"CDKL5-Related Disorders: From Clinical Description to Molecular Genetics","volume":"2","author":"Bienvenu","year":"2012","journal-title":"Mol. 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