Rett syndrome is an X chromosome-linked neurodevelopmental disorder associated with cognitive impairment and severe breathing irregularities causing intermittent hypoxic episodes. Recently, we detected an increased hypoxia-susceptibility of Rett mouse (MeCP2^-/y) hippocampus. Underlying mechanisms include K⁺-channel dysregulation and disturbed Ca²⁺-homeostasis. Furthermore, mitochondrial disturbance can be assumed. Among the MeCP2-controlled genes is a complex III subunit. Also, a proton leak across the inner mitochondrial membrane and reduced brain ATP levels were reported. Furthermore, patient blood samples were found to show increased lipid peroxidation and lowered superoxide dismutase activity. We therefore screened for mitochondrial dysfunction and increased oxidative burden in Rett mice. Monitoring autofluorescence in hippocampal slices revealed increased FAD/NADH baseline-ratios in MeCP2^-/y mice, indicating intensified oxidization. Mitochondrial poisoning with CN^- caused similar decreases in FAD/NADH ratio and mitochondrial membrane potential (rhodamine123 fluorescence) in both genotypes. To assess cytosolic redox conditions, we used the genetically-engineered optical probe roGFP1. Its calibration in organotypic hippocampal slices confirmed similar responses to pronounced oxidation/reduction in both genotypes. However, redox baseline levels suggest more oxidized conditions in MeCP2^-/y hippocampus. For optimized roGFP1 expression and selective neuronal targeting, a recombinant adenovirus was designed, placing the roGFP1-enconding DNA under the control of the synapsin promoter. First trials confirmed markedly improved expression rates but lower expression levels than compared with lipofectamine. In conclusion, Rett mouse hippocampus suffers from a more pronounced oxidative burden that apparently arises from dysfunctioning mitochondria. Since several receptors and ion-channels are redox-sensitive this oxidative shift might contribute to the hyperexcitability and disturbed synaptic plasticity in Rett syndrome.