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We previously identified aberrant NF-\u03baB pathway upregulation in brains of<jats:italic>Mecp2<\/jats:italic>-null mice and demonstrated that genetically attenuating NF-\u03baB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-\u03baB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-\u03baB pathway inhibitor vitamin D ameliorates neuronal phenotypes in<jats:italic>Mecp2<\/jats:italic>-mutant mice. Vitamin D deficiency is prevalent among RTT patients, and we find that<jats:italic>Mecp2<\/jats:italic>-null mice similarly have significantly reduced 25(OH)D serum levels compared with wild-type littermates. We identify that vitamin D rescues aberrant NF-\u03baB pathway activation and reduced neurite outgrowth of<jats:italic>Mecp2<\/jats:italic>knock-down cortical neurons<jats:italic>in vitro<\/jats:italic>. Further, dietary supplementation with vitamin D in early symptomatic male<jats:italic>Mecp2<\/jats:italic>hemizygous null and female<jats:italic>Mecp2<\/jats:italic>heterozygous mice ameliorates reduced neocortical dendritic morphology and soma size phenotypes and modestly improves reduced lifespan of<jats:italic>Mecp2<\/jats:italic>-nulls. These results elucidate fundamental neurobiology of RTT and provide foundation that NF-\u03baB pathway inhibition might be a therapeutic target for RTT.<\/jats:p>","DOI":"10.1523\/eneuro.0167-20.2020","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T21:49:30Z","timestamp":1589233770000},"page":"ENEURO.0167-20.2020","source":"Crossref","is-referenced-by-count":25,"title":["Vitamin D Supplementation Rescues Aberrant NF-\u03baB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in<i>Mecp2<\/i>Mutant Mice"],"prefix":"10.1523","volume":"7","author":[{"given":"Mayara C.","family":"Ribeiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth 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