Impaired hippocampal Ca 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 (K_ATP-) 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 K_ATP- 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 K_Ca 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 K_Ca 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.