TY - JOUR T1 - Vitamin D Supplementation Rescues Aberrant NF-κB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in <em>Mecp2</em> Mutant Mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0167-20.2020 VL - 7 IS - 3 SP - ENEURO.0167-20.2020 AU - Mayara C. Ribeiro AU - Seth M. Moore AU - Noriyuki Kishi AU - Jeffrey D. Macklis AU - Jessica L. MacDonald Y1 - 2020/05/01 UR - http://www.eneuro.org/content/7/3/ENEURO.0167-20.2020.abstract N2 - Rett syndrome (RTT) is a severe, progressive X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. We previously identified aberrant NF-κB pathway upregulation in brains of Mecp2-null mice and demonstrated that genetically attenuating NF-κB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-κB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-κB pathway inhibitor vitamin D ameliorates neuronal phenotypes in Mecp2-mutant mice. Vitamin D deficiency is prevalent among RTT patients, and we find that Mecp2-null mice similarly have significantly reduced 25(OH)D serum levels compared with wild-type littermates. We identify that vitamin D rescues aberrant NF-κB pathway activation and reduced neurite outgrowth of Mecp2 knock-down cortical neurons in vitro. Further, dietary supplementation with vitamin D in early symptomatic male Mecp2 hemizygous null and female Mecp2 heterozygous mice ameliorates reduced neocortical dendritic morphology and soma size phenotypes and modestly improves reduced lifespan of Mecp2-nulls. These results elucidate fundamental neurobiology of RTT and provide foundation that NF-κB pathway inhibition might be a therapeutic target for RTT. ER -