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 (K(ATP-)) and big-conductance Ca(2+)-activated K(+) channels (BK-channels) did not affect the early anoxic hyperpolarization in either genotype. However, blocking Ca(2+) 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 Ca(2+)-dependently activated various small/intermediate-conductance K(+) channels in WT neurons, which was less evident in Mecp2(-/y) neurons. Yet, pharmacologically increasing the Ca(2+) sensitivity of small/intermediate-conductance K(Ca) channels fully restored the anoxic hyperpolarization in Mecp2(-/y) neurons. Furthermore, Ca(2+) imaging unveiled lower intracellular Ca(2+) levels in resting Mecp2(-/y) neurons and reduced anoxic Ca(2+) transients with diminished Ca(2+) release from intracellular stores. In conclusion, the enhanced hypoxia susceptibility of Mecp2(-/y) hippocampus is primarily associated with disturbed Ca(2+) homeostasis and diminished Ca(2+) 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 Ca(2+) levels also determine neuronal excitability and synaptic plasticity, Ca(2+) homeostasis may constitute a promising target for pharmacotherapy in RTT.
Kron
M
M
DFG Research Center Molecular Physiology of the Brain, Abteilung Neuro- und Sinnesphysiologie, Georg-August-Universität Göttingen, Humboldtallee 23, D-37073 Göttingen, Germany.
Müller
M
M
D000704:Analysis of Variance; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D018999:Charybdotoxin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency; D003620:Dantrolene / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000009:adverse effects; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D000860:Hypoxia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics / Q000503:physiopathology*; D012966:Sodium Cyanide / Q000009:adverse effects
D001577:Benzophenones; D001896:Boron Compounds; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C489326:Mbd2 protein, mouse; D009125:Muscle Relaxants, Central; D009498:Neurotoxins; D015221:Potassium Channels; D018999:Charybdotoxin; C109986:2-aminoethoxydiphenyl borate; D003620:Dantrolene; C121479:2,4-dihydroxybenzophenone; D012966:Sodium Cyanide; D002118:Calcium