Rett syndrome is a neurodevelopmental disorder caused by mutations the X chromosome-linked MECP2 gene that encodes for the transcriptional regulator methyl CpG binding protein 2. Rett patients suffer from respiratory irregularities, i.e. episodes of reduced arterial oxygen levels. It is unclear, however, whether such frequent hypoxic episodes may induce adaptation of highly vulnerable neuronal networks to oxygen shortage. Therefore, changes in synaptic function and in the hypoxic responses of mouse hippocampal slices were quantified. Basal synaptic function was intact, whereas paired pulse facilitation was reduced in MeCP2 KO males but not in heterozygous females. Inducing hypoxic spreading depression (HSD)- a model for ischemic stroke - did not reveal any marked differences in the characteristic electrophysiological and optical signs, with the exception that HSD onset was slightly hastened in MeCP2 KO males. Hypoxia- induced synaptic failure was complete in all groups within 2 min after oxygen withdrawal. Upon reoxygenation, synaptic function recovered slowest in WT females, whereas MeCP2 KO males showed transiently potentiated fEPSPs. The final degree of synaptic recovery did, however, not differ among the different groups. Since the onset of HSD was slightly hastened in male MeCP2 KO mice, an adaptation to hypoxia resulting in increased hypoxia tolerance can be ruled out for the hippocampal formation. Rather the outcome of stroke may be worse.