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Rett syndrome (RTT) is a neurodevelopmental disease in children that is mainly caused by mutations in the MeCP2 gene, which codes for a transcriptional regulator. The expression of insulin-like growth factor-1 (IGF-1) is reduced in RTT patients and animal models, and IGF-1 treatment is a promising therapeutic strategy for RTT. However, the mechanism underlying the effects of IGF-1 remains to be further explored. FXYD1 is an auxiliary subunit of Na, K-ATPase. Overexpression of FXYD1 is involved in the pathogenesis of RTT. However, whether IGF-1 exerts its effect through normalizing FXYD1 is completely unknown. To this end, we evaluated the effect of IGF-1 on FXYD1 expression and posttranslational modification in a mouse model of RTT (MeCP2308) using both in vitro and in vivo experiments. The results show that FXYD1 mRNA and phosphorylated protein (p-FXYD1) were significantly elevated in the frontal cortex in RTT mice, compared to wild type. In RTT mice, IGF-1 treatment significantly reduced levels of FXYD1 mRNA and p-FXYD1, in parallel with improvements in behavior, motor coordination, and cognitive function. For mechanistic insight into the effect of IGF-1 on p-FXYD1, we found the decreased phosphorylated forms of PI3K-AKT-mTOR signaling pathway components in the frontal cortex of RTT mice and the normalizing effect of IGF-1 on the phosphorylated forms of these components. Interestingly, blocking the PI3K/AKT pathway by PI3K inhibitor could abolish the effect of IGF-1 on p-FXYD1 level, in addition to the effect of IGF-1 on the phosphorylation of other components in the PI3K/AKT pathway. Thus, our study has provided new insights into the mechanism of IGF-1 treatment for RTT, which appears to involve FXYD1.

Background: Tic disorders (TD) are common neuropsychiatric disorders among children and adolescents. It is controversial that trace elements may participate in the pathogenesis of TD. Our study aimed to investigate the trace elements status of zinc (Zn), copper (Cu), iron (Fe), and magnesium (Mg) in children with TD, in comparison to healthy controls.Methods: The medical records of eligible TD children and normal healthy children from January 1 to December 31, 2018 in the outpatient clinic were retrospectively reviewed. The clinical information of all subjects were collected including age, gender, diagnosis, previous health records, and serum trace elements level (Cu, Zn, Fe, Mg) at the time of diagnosis before initiating treatment.Results: In total, 1204 TD children (7.63 ± 2.45 years) and 1,220 healthy children (7.27 ± 3.15 years) who were divided into two gender and three age groups (2–4years, 5–9years, ≥10 years) were reviewed in our study. Our study showed that TD children generally had lower whole blood levels of Zn, Cu, Fe than the normal controls (P < 0.01). No significant difference was observed in whole blood levels of Mg. After adjusting for gender, the trends still remained. Further analysis was performed according to age, the trends still remained in Zn and Fe in all age groups (P < 0.05). However, we observed an almost significantly (P = 0.055) lower level of Cu in TD of 2–4 years group while significant differences in other two groups (P < 0.01). Further multiple linear regression and point biserial correlation showed that the lower blood levels of Zn, Cu, and Fe were correlated with the incidence of TD.Conclusion: The present results indicated that lower blood levels of zinc, iron, copper were associated with TD. Trace elements may be used as an auxiliary treatment for TD and need to be further explored.

β-Catenin is a key component of the canonical Wnt signaling pathway. It has been shown to have an important role in formation of the neuromuscular junction. Our previous studies showed that in the absence of β-catenin, the resting membrane potential (RMP) is depolarized in muscle cells and expression of the α2 subunit of sodium/potassium adenosine triphosphatase (α2NKA) is reduced. To understand the underlying mechanisms, we investigated the electrophysiologic properties of a primary cell line derived from mouse myoblasts (C2C12 cells) that were transfected with small-interfering RNAs and over-expressed plasmids targeting β-catenin. We found that the RMP was depolarized in β-catenin knocked-down C2C12 cells and was unchanged in β-catenin over-expressed muscle cells. An action potential (AP) was not released by knockdown or over-expression of β-catenin. α2NKA expression was reduced by β-catenin knockdown, and increased by β-catenin over-expression. We showed that β-catenin could interact physically with α2NKA (but not with α1NKA) in muscle cells. NKA activity and α2NKA content in the cell membranes of skeletal muscle cells were modulated positively by β-catenin. These results suggested that β-catenin (at least in part) regulates the RMP and AP in muscle cells, and does so by regulating α2NKA.