Vitamin d supplementation rescues aberrant nf-kb pathway activation and partially ameliorates rett syndrome phenotypes in mecp2 mutant mice

Abstract

Rett syndrome (RTT) is a severe, progressive X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. We previously identified aberrant NF-kB pathway upregulation in brains of Mecp2-null mice and demonstrated that genetically attenuating NF-kB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-kB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-kB pathway inhibitor vitamin D ameliorates neuronal phenotypes in Mecp2-mutant mice. Vitamin D deficiency is prevalent among RTT pa-tients, 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-kB 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-kB pathway inhibition might be a therapeutic target for RTT.