{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T19:57:27Z","timestamp":1781726247039,"version":"3.54.5"},"reference-count":61,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T00:00:00Z","timestamp":1571356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Japanese Society for the Promotion of Science","award":["26463120 and 18K09846"],"award-info":[{"award-number":["26463120 and 18K09846"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["18059228"],"award-info":[{"award-number":["18059228"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The deletion of Mecp2, the gene encoding methyl-CpG-binding protein 2, causes severe breathing defects and developmental anomalies in mammals. In Mecp2-null mice, impaired GABAergic neurotransmission is demonstrated at the early stage of life. GABAergic dysfunction in neurons in the rostral ventrolateral medulla (RVLM) is considered as a primary cause of breathing abnormality in Mecp2-null mice, but its molecular mechanism is unclear. Here, we report that mRNA expression levels of Gad1, which encodes glutamate decarboxylase 67 (GAD67), in the RVLM of Mecp2-null (Mecp2-\/y, B6.129P2(C)-Mecp2tm1.1Bird\/J) mice is closely related to the methylation status of its promoter, and valproate (VPA) can upregulate transcription from Gad1 through epigenetic mechanisms. The administration of VPA (300 mg\/kg\/day) together with L-carnitine (30 mg\/kg\/day) from day 8 to day 14 after birth increased Gad1 mRNA expression in the RVLM and reduced apnea counts in Mecp2-\/y mice on postnatal day 15. Cytosine methylation levels in the Gad1 promoter were higher in the RVLM of Mecp2-\/y mice compared to wild-type mice born to C57BL\/6J females, while VPA treatment decreased the methylation levels in Mecp2-\/y mice. Chromatin immunoprecipitation assay revealed that the VPA treatment reduced the binding of methyl-CpG binding domain protein 1 (MBD1) to the Gad1 promoter in Mecp2-\/y mice. These results suggest that VPA improves breathing of Mecp2-\/y mice by reducing the Gad1 promoter methylation, which potentially leads to the enhancement of GABAergic neurotransmission in the RVLM.<\/jats:p>","DOI":"10.3390\/ijms20205177","type":"journal-article","created":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T11:24:15Z","timestamp":1571397855000},"page":"5177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice"],"prefix":"10.3390","volume":"20","author":[{"given":"Misa","family":"Ishiyama","sequence":"first","affiliation":[{"name":"Department of Pediatric Dentistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisanori","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Takei","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Hoshi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatake","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Pathology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9536-7160","authenticated-orcid":false,"given":"Tetsuo","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. 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