Whilst Mecp2-knockout mice display many of the neurological features seen in Rett patients (motor impairments and abnormal breathing), there are important differences in Rett-like phenotypes in mice and those observed in patients. In particular, females with RTT develop symptoms as young children whereas heterozygous Mecp2-KO mice develop overt phenotypes late on in adulthood and they are generally much

milder. For instance, spontaneous seizures and autonomic abnormalities are common in patients but rarely seen in mice. As such RTT-like FK506 ic50 phenotypes in mice are considered much less severe and in this respect is could be argued that the RTT-like phenotypes seen in male Mecp2-KO mice are somewhat closer to the clinical picture (juvenile onset of symptoms which then become very severe) although, like RTT in male patients, the consequence of mutation/KO is invariably fatal beyond early/mid this website adulthood. Whilst we have not observed overt signs of spontaneous fractures in experimental colonies of mice, such a magnitude of reduced bone stiffness and load properties could mirror the 4 times increased risk of fracture in Rett patients compared to the population rate [15]. That a similar reduction in microhardness (and a trend towards reduced biomechanical properties) was seen in female mice ( Fig. 4, Fig. 5 and Fig. 7)

that are heterozygous and mosaic for the mutant allele, demonstrate that the bone deficits are not restricted to the more severe male RTT-like phenotype but are seen in a gender and MeCP2 expression pattern appropriate model of RTT, albeit one that is milder than RTT in human females. Analysis of femoral

neck fracture showed no difference between genotypes. It is possible that the complex microstructure of bone in the femoral neck (cf. the simple cortical shaft geometry) is a confounding factor and limits the sensitivity of this test. Indeed, we also noted greater variance in this test than in the other biomechanical tests which may also limit our ability many to resolve subtle changes in this parameter. However, it is also possible that any deficits are too subtle to be detected given the power of the current study. Whilst group sizes of the order used in the current experiments enable the unambiguous detection of overt neurological phenotypes, it is likely that bone phenotypes are more subtle and that much larger group sizes would be required to detect subtle changes in histological and biomechanical phenotypes, especially in heterozygous Mecp2+/− mice. An important finding of the current study and one with therapeutic implications is that the observed deficits in cortical bone material and biomechanical properties were rescued by delayed postnatal activation of the Mecp2 gene.