Source:http://linkedlifedata.com/resource/pubmed/id/20732392
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
2010-10-18
|
| pubmed:abstractText |
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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2,4-dihydroxybenzophenone,
http://linkedlifedata.com/resource/pubmed/chemical/2-aminoethoxydiphenyl borate,
http://linkedlifedata.com/resource/pubmed/chemical/Benzophenones,
http://linkedlifedata.com/resource/pubmed/chemical/Boron Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Charybdotoxin,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Dantrolene,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Mbd2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Muscle Relaxants, Central,
http://linkedlifedata.com/resource/pubmed/chemical/Neurotoxins,
http://linkedlifedata.com/resource/pubmed/chemical/Potassium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Sodium Cyanide
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Nov
|
| pubmed:issn |
1873-7544
|
| pubmed:author | |
| pubmed:copyrightInfo |
Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
|
| pubmed:issnType |
Electronic
|
| pubmed:day |
24
|
| pubmed:volume |
171
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
300-15
|
| pubmed:meshHeading |
pubmed-meshheading:20732392-Analysis of Variance,
pubmed-meshheading:20732392-Animals,
pubmed-meshheading:20732392-Anoxia,
pubmed-meshheading:20732392-Benzophenones,
pubmed-meshheading:20732392-Biophysical Processes,
pubmed-meshheading:20732392-Boron Compounds,
pubmed-meshheading:20732392-Calcium,
pubmed-meshheading:20732392-Charybdotoxin,
pubmed-meshheading:20732392-DNA-Binding Proteins,
pubmed-meshheading:20732392-Dantrolene,
pubmed-meshheading:20732392-Disease Models, Animal,
pubmed-meshheading:20732392-Dose-Response Relationship, Drug,
pubmed-meshheading:20732392-Electric Stimulation,
pubmed-meshheading:20732392-Enzyme Inhibitors,
pubmed-meshheading:20732392-Hippocampus,
pubmed-meshheading:20732392-Homeostasis,
pubmed-meshheading:20732392-Membrane Potentials,
pubmed-meshheading:20732392-Mice,
pubmed-meshheading:20732392-Mice, Inbred C57BL,
pubmed-meshheading:20732392-Mice, Knockout,
pubmed-meshheading:20732392-Muscle Relaxants, Central,
pubmed-meshheading:20732392-Neurons,
pubmed-meshheading:20732392-Neurotoxins,
pubmed-meshheading:20732392-Patch-Clamp Techniques,
pubmed-meshheading:20732392-Potassium Channels,
pubmed-meshheading:20732392-Rett Syndrome,
pubmed-meshheading:20732392-Sodium Cyanide
|
| pubmed:year |
2010
|
| pubmed:articleTitle |
Impaired hippocampal Ca2+ homeostasis and concomitant K+ channel dysfunction in a mouse model of Rett syndrome during anoxia.
|
| pubmed:affiliation |
DFG Research Center Molecular Physiology of the Brain, Abteilung Neuro- und Sinnesphysiologie, Georg-August-Universität Göttingen, Humboldtallee 23, D-37073 Göttingen, Germany.
|
| pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
|