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The Journal of Neuroscience, June 13, 2007, 27(24):6581-6589; doi:10.1523/JNEUROSCI.0338-07.2007

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Cellular/Molecular
Leukoencephalopathy upon Disruption of the Chloride Channel ClC-2

Judith Blanz,¹ Michaela Schweizer,¹ Muriel Auberson,^1,4 Hannes Maier,³ Adrian Muenscher,³ Christian A. Hübner,^1,2 and Thomas J. Jentsch^1,4

¹Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Universität Hamburg, D-20252 Hamburg, Germany, ²Institut für Humangenetik and ³Klinik für Hals-, Nasen- und Ohrenheilkunde (HNO), Universitätsklinik Hamburg-Eppendorf, D-20246 Hamburg, Germany, and ⁴Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany

Correspondence should be addressed to either of the following: Dr. Thomas J. Jentsch, Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Straße 10, D-13125 Berlin, Germany, Email: Jentsch{at}fmp-berlin.de; or Dr. Christian A. Hübner, Friedrich-Schiller-Universität Jena, Institut für Klinische Chemie und Laboratoriumsmedizin, Erlangeralle 101, D-07747 Jena, Germany, Email: christian.huebner{at}med.uni-jena.de

ClC-2 is a broadly expressed plasma membrane chloride channel that is modulated by voltage, cell swelling, and pH. A human mutation leading to a heterozygous loss of ClC-2 has previously been reported to be associated with epilepsy, whereas the disruption of Clcn2 in mice led to testicular and retinal degeneration. We now show that the white matter of the brain and spinal cord of ClC-2 knock-out mice developed widespread vacuolation that progressed with age. Fluid-filled spaces appeared between myelin sheaths of the central but not the peripheral nervous system. Neuronal morphology, in contrast, seemed normal. Except for the previously reported blindness, neurological deficits were mild and included a decreased conduction velocity in neurons of the central auditory pathway. The heterozygous loss of ClC-2 had no detectable functional or morphological consequences. Neither heterozygous nor homozygous ClC-2 knock-out mice had lowered seizure thresholds. Sequencing of a large collection of human DNA and electrophysiological analysis showed that several ClC-2 sequence abnormalities previously found in patients with epilepsy most likely represent innocuous polymorphisms.

Key words: leukodystrophy; oligodendrocyte; glia; knock-out; anion transport; ion siphoning

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Received Jan. 25, 2007; revised April 9, 2007; accepted May 3, 2007.

Correspondence should be addressed to either of the following: Dr. Thomas J. Jentsch, Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Straße 10, D-13125 Berlin, Germany, Email: Jentsch{at}fmp-berlin.de; or Dr. Christian A. Hübner, Friedrich-Schiller-Universität Jena, Institut für Klinische Chemie und Laboratoriumsmedizin, Erlangeralle 101, D-07747 Jena, Germany, Email: christian.huebner{at}med.uni-jena.de

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