Impaired hippocampal Ca2+ homeostasis and concomitant K+ channel dysfunction in a mouse model of rett syndrome during anoxia

Methyl-CpG-binding protein 2 (MeCP2) deficiency causes Rett syndrome (RTT), a neurodevelopmental disorder characterized by severe cognitive impairment, synaptic dysfunction, and hyperexcitability. Previously we reported that the hippocampus of MeCP2-deficient mice (Mecp2−/y), a mouse model for RTT, is more susceptible to hypoxia. To identify the underlying mechanisms we now focused on the anoxic responses of wildtype (WT) and Mecp2−/y CA1 neurons in acute hippocampal slices. Intracellular recordings revealed that Mecp2−/y neurons show only reduced or no hyperpolarizations early during cyanide-induced anoxia, suggesting potassium channel (K+ channel) dysfunction. Blocking adenosine-5′-triphosphate-sensitive K+ channels (KATP-) and big-conductance Ca2+-activated K+ channels (BK-channels) did not affect the early anoxic hyperpolarization in either genotype. However, blocking Ca2+ release from the endoplasmic reticulum almost abolished the anoxic hyperpolarizations in Mecp2−/y neurons. Single-channel recordings confirmed that neither KATP- nor BK-channels are the sole mediators of the early anoxic hyperpolarization. Instead, anoxia Ca2+-dependently activated various small/intermediate-conductance K+ channels in WT neurons, which was less evident in Mecp2−/y neurons. Yet, pharmacologically increasing the Ca2+ sensitivity of small/intermediate-conductance KCa channels fully restored the anoxic hyperpolarization in Mecp2−/y neurons. Furthermore, Ca2+ imaging unveiled lower intracellular Ca2+ levels in resting Mecp2−/y neurons and reduced anoxic Ca2+ transients with diminished Ca2+ release from intracellular stores. In conclusion, the enhanced hypoxia susceptibility of Mecp2−/y hippocampus is primarily associated with disturbed Ca2+ homeostasis and diminished Ca2+ rises during anoxia. This secondarily attenuates the activation of KCa channels and thereby increases the hypoxia susceptibility of Mecp2−/y neuronal networks. Since cytosolic Ca2+ levels also determine neuronal excitability and synaptic plasticity, Ca2+ homeostasis may constitute a promising target for pharmacotherapy in RTT.