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The Journal of Neuroscience, August 1, 2001, 21(15):5429-5438

Kir4.1 Potassium Channel Subunit Is Crucial for Oligodendrocyte Development and In Vivo Myelination

Clemens Neusch¹, Nora Rozengurt², Russell E. Jacobs¹, Henry A. Lester¹, and Paulo Kofuji³

¹ Division of Biology, California Institute of Technology, Pasadena, California 91125, ² Department of Pathology, University of California Los Angeles School of Medicine, Los Angeles, California 90095, and ³ Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455

To understand the cellular and in vivo functions of specific K⁺ channels in glia, we have studied mice with a null mutation in the weakly inwardly rectifying K⁺ channel subunit Kir4.1. Kir4.1/ mice display marked motor impairment, and the cellular basis is hypomyelination in the spinal cord, accompanied by severe spongiform vacuolation, axonal swellings, and degeneration. Immunostaining in the spinal cord of wild-type mice up to postnatal day 18 reveals that Kir4.1 is expressed in myelin-synthesizing oligodendrocytes, but probably not in neurons or glial fibrillary acidic protein-positive (GFAP-positive) astrocytes. Cultured oligodendrocytes from developing spinal cord of Kir4.1/ mice lack most of the wild-type K⁺ conductance, have depolarized membrane potentials, and display immature morphology. By contrast, cultured neurons from spinal cord of Kir4.1/ mice have normal physiological characteristics. We conclude that Kir4.1 forms the major K⁺ conductance of oligodendrocytes and is therefore crucial for myelination. The Kir4.1 knock-out mouse is one of the few CNS dysmyelinating or demyelinating phenotypes that does not involve a gene directly involved in the structure, synthesis, degradation, or immune response to myelin. Therefore, this mouse shows how an ion channel mutation could contribute to the polygenic demyelinating diseases.

Key words: oligodendrocytes; myelination; inwardly rectifying potassium channels; knock-out mouse; glia; spinal cord

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21155429-10$05.00/0

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