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Evidence that compromised K+ spatial buffering contributes to the epileptogenic effect of mutations in the human kir4.1 gene (KCNJ10)

Authors

  • Nadia Nabil Haj-Yasein,

    1. Centre for Molecular Biology and Neuroscience, Letten Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
    2. Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
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  • Vidar Jensen,

    1. Centre for Molecular Biology and Neuroscience, Letten Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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  • Gry Fluge Vindedal,

    1. Centre for Molecular Biology and Neuroscience, Letten Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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  • Georg Andreas Gundersen,

    1. Centre for Molecular Biology and Neuroscience, Letten Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
    2. Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
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  • Arne Klungland,

    1. Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Oslo University Hospital, Oslo, Norway
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  • Ole Petter Ottersen,

    1. Centre for Molecular Biology and Neuroscience, Letten Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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  • Øivind Hvalby,

    1. Centre for Molecular Biology and Neuroscience, Letten Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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  • Erlend Arnulf Nagelhus

    Corresponding author
    1. Centre for Molecular Biology and Neuroscience, Letten Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
    2. Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
    3. Oslo University Hospital, Department of Neurology, Oslo, Norway
    4. Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York
    • Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, PO Box 1137 Blindern, N-0318 Oslo, Norway
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Abstract

Mutations in the human Kir4.1 potassium channel gene (KCNJ10) are associated with epilepsy. Using a mouse model with glia-specific deletion of Kcnj10, we have explored the mechanistic underpinning of the epilepsy phenotype. The gene deletion was shown to delay K+ clearance after synaptic activation in stratum radiatum of hippocampal slices. The activity-dependent changes in extracellular space volume did not differ between Kcnj10 mutant and wild-type mice, indicating that the Kcnj10 gene product Kir4.1 mediates osmotically neutral K+ clearance. Combined, our K+ and extracellular volume recordings indicate that compromised K+ spatial buffering in brain underlies the epilepsy phenotype associated with human KCNJ10 mutations. © 2011 Wiley-Liss, Inc.

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