There is currently no effective treatment for Rett syndrome (RTT), a severe X-linked progressive neurodevelopmental disorder (NDD) caused by mutations in the transcriptional regulator MECP2. Hence, the overall goal of this proposal is to understand the underlying pathophysiology of RTT, and identify novel therapeutic avenues for this devastating disorder. Mecp2 mutant mice (male null mice, and female heterozygous mice) exhibit a range of neurological abnormalities that recapitulate the human disorder, including reduced neuronal dendritic complexity and soma size, and severe motor deficits. Importantly, 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 downstream therapeutic target is NF-?B. My previous work demonstrated that a consequence of Mecp2 loss of function is up-regulation of Irak1, leading to aberrant NF-?B signaling (Kishi* and MacDonald* et al, Nature Communications 2016). Strikingly, genetically reducing the NF-?B pathway in Mecp2-null male mice partially rescues their reduced cortical dendritic complexity and substantially extends their normally shortened lifespan. Further, our preliminary data demonstrate that dietary supplementation with the NF-?B inhibitor vitamin D (VitD) partially rescues Mecp2-null phenotypes in male mice. Intriguingly, VitD deficiency is highly prevalent in RTT patients, and has been implicated in multiple other NDDs, including autism spectrum disorders (ASD). We thus hypothesize that attenuation of NF-?B signaling, via dietary supplementation with VitD, could have broad therapeutic benefit in RTT, and potentially other neurological disorders with overlapping pathology. We propose to test our hypotheses by comparing the in vivo therapeutic potential of VitD supplementation and genetic attenuation of NF-?B in female Mecp2 heterozygous mice (Aim 1), determining whether vitamin D supplementation rescues RTT cortical neuronal phenotypes via cell autonomous or cell-non-autonomous mechanisms (Aim 2), and determining underlying molecular mechanisms of this phenotypic rescue (Aim 3). We will take a unique, integrative approach, investigating phenotypic rescue from the molecular (transcriptome) and cellular level, to the level of neuronal and dendritic connectivity, to behavior. Although VitD supplementation may not provide a ?cure? for RTT, any phenotypic improvement from such a simple, cost-effective supplement would be extremely exciting, with the potential for quality of life improvements. Further, we will identify molecular mechanisms underpinning the phenotypic improvements, which could lead to additional new therapeutic targets, for RTT and other neurological disorders with overlapping pathology.
/ RELEVANCE There is currently no effective treatment for Rett syndrome, a severe, progressive neurodevelopmental disorder resulting from mutations in the gene MECP2. Previously, my colleagues and I identified that an important signaling pathway, NF-?B, is aberrantly up-regulated in the brain of Mecp2-mutant mice and, strikingly, we found that genetically reducing NF-?B signaling in these mice improves some of the characteristic neuronal phenotypes in Rett syndrome, and significantly extends their normally shortened lifespan. These results strongly suggest that inhibition of NF-?B signaling could provide a therapeutic avenue in Rett syndrome; importantly, many inhibitors of this signaling pathway have already been identified, including vitamin D - a simple, cost-effective dietary supplement. We propose to investigate the therapeutic potential of vitamin D supplementation and NF- ?B pathway inhibition in Mecp2-mutant mice and to identify mechanisms underlying phenotypic rescue; the overall goal is to understand the underlying pathology of Rett syndrome and identify novel therapeutic targets.