Vitamin D supplementation rescues aberrant NF-κB 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-κB pathway up-regulation 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 to wildtype littermates. We identify that vitamin D rescues aberrant NF-κB pathway activation and reduced neurite outgrowth of Mecp2 knockdown 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.

Significance Statement There is currently no effective treatment for Rett syndrome (RTT); however, selectively re-expressing Mecp2 in adult mice has shown that RTT symptoms can be partially reversed, suggesting that restoration of homeostasis of downstream targets of MeCP2 could also reverse or alleviate RTT symptoms. One such potential target is the NF-κB pathway, which is aberrantly up-regulated in the brain of Mecp2-mutant mice. Genetically reducing NF-κB signaling in these mice improves neuronal phenotypes. Here, we identify that the known NF-κB inhibitor vitamin D reduces the aberrant NF-κB signaling in Mecp2 knockdown neurons, and partially ameliorates neuronal size and complexity phenotypes in both male and female Mecp2-mutant mice. Thus, this simple, cost-effective dietary supplement could contribute toward a partial therapeutic avenue in RTT.