Objectives: Mecp2-deficiency causes Rett syndrome, a neurodevelopmental disorder leading to severe cognitive disabilities. Our recent work revealed that the hippocampal formation of male MeCP2-deficient mice (KO) is more susceptible to severe hypoxia. Here, we studied the underlying mechanisms in more detail. Methods: Anoxic responses induced by 0.1–1 mM NaCN of wildtype (WT) and KO hippocampal neurons were analyzed in acute tissue slices performing intracellular recordings, single-channel recordings and Ca²⁺-imaging. Results: During anoxia, KO neurons show only reduced or no early hyperpolarization, suggesting K⁺-channel dysfunction (WT: -7.2 ± 3.1 mV, KO: 4.5 ± 4.1 mV). Blockers of K_ATP- and BK-channels did not modify the anoxic hyperpolarizations in WT and KO neurons. Single-channel recordings confirmed that neither K_ATP- nor BK-channels alone mediate the anoxic hyperpolarizations. Rather, various K⁺-channels became activated during anoxia in WT patches (NPo 14.4 ± 17.6%) in a Ca²⁺-dependent manner, yet their activation was less pronounced in KO patches (NPo 3.2 ± 3.2%) . Blocking Ca²⁺ release from the endoplasmic reticulum almost abolished the anoxic hyperpolarization of KO neurons (-1.4 ± 1.6 mV), suggesting disturbed Ca²⁺-homeostasis in KO neurons. Ca²⁺-imaging confirmed lower Ca²⁺ at rest and reduced anoxic Ca²⁺-rises in KO compared to WT neurons (+309.4 ± 134.6 nM vs. 204.8 ± 90.8 nM). Removing extracellular Ca²⁺ confirmed a diminished Ca²⁺-release from intracellular stores during anoxia. Conclusions: The enhanced hypoxia susceptibility observed in the hippocampus of Rett mice is primarily due to disturbed Ca²⁺-homeostasis and diminished Ca²⁺-rises during anoxia. This may secondarily attenuate the activation of neuroprotective Ca²⁺-dependent K⁺-channels and thus impair the hypoxia tolerance of MeCP2-deficient neuronal networks. Supported by the DFG (CMPB)