Rett syndrome is a neurodevelopmental disorder associated with cognitive dysfunction, motor deficits and respiratory disturbances leading to intermittent episodes of systemic hypoxia. Objectives: In a Rett mouse model, we previously detected an increased hypoxia susceptibility of the hippocampal formation. Therefore, we now elucidated whether also medullarly networks would be more susceptible to hypoxia. Methods: Brainstem slices of infant Rett mice (p10-15) were exposed to severe hypoxia. Extracellular DC potential as well as the intrinsic optical signal (IOS) were monitored to detect hypoxia- induced spreading depression (HSD). Results: HSD was preferably ignited within the nucleus tractus solitarius (NTS) and then spread towards the sagittal midline and the lateral and ventral slice regions. In rhythmically active slices, propagation of HSD into the ventral respiratory group abolished the in vitro respiratory rhythm for several minutes. Upon increased extracellular K⁺ levels (8 mM), HSD was ignited at various sites within the brainstem, and the onset of HSD was hastened in Mecp2^-/y slices by ~30% as compared to WT slices. In 3.5 mM K⁺ solutions, HSD onset did not differ. Analysis of the HSD- associated IOS did not yield any genotype- specific differences of HSD ignition, propagation and tissue invasion. Since 5-HT receptor modulation may stabilize the respiratory network under pathophysiological conditions, we pretreated slices with the 5 HT_1A receptor agonist 8-OH DPAT (8- hydroxy-2-(di-n-propylamino) tetralin). Indeed, such pretreatment postponed the occurrence of HSD in WT and Mecp2^-/y slices by 16%. Conclusion: Medullary networks of Rett mice are more susceptible to hypoxia when oxygen shortage coincides with other challenges, e.g. increased extracellular K⁺ levels. 5- HT_1A receptor stimulation may provide some degree of protection against the occurrence of HSD and the associated arrest of respiratory rhythmogenesis.