Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both -/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.

Rett syndrome (RTT) is a neurodevelopmental disorder, primarily affecting girls. RTT causes severe cognitive, social, motor and physiological impairments and no cure currently exists. The discovery of a monogenic origin for RTT and the subsequent generation of RTT mouse models provided a major breakthrough for RTT research. Although the characterization of these mutant mice is far from complete, they recapitulate several RTT symptoms. This review provides an overview of the behavioural domains so far investigated in these models, including the very few mouse data concerning the developmental course of RTT. Both clinical and animal studies support the presence of early defects and highlight the importance of probing the presymptomatic phase for both the precocious identification of biomarkers and the early assessment of potential therapies. Preclinical evaluations of pharmacological and nonpharmacological interventions so far carried out are also illustrated. In addition, genetic manipulations are reported that demonstrate rescue from the damage caused by the absence of the methyl-CpG-binding protein 2 (MeCP2) gene even at a mature stage. Given the rare occurrence of RTT cases, transnational collaborative networks are expected to provide a deeper understanding of aetiopathology and the development of new therapeutic approaches.