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Loss of K‐Cl co‐transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold
Author(s) -
Boettger Thomas,
Rust Marco B.,
Maier Hannes,
Seidenbecher Thomas,
Schweizer Michaela,
Keating Damien J.,
Faulhaber Jörg,
Ehmke Heimo,
Pfeffer Carsten,
Scheel Olaf,
Lemcke Beate,
Horst Jürgen,
Leuwer Rudolf,
Pape HansChristian,
Völkl Harald,
Hübner Christian A.,
Jentsch Thomas J.
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg519
Subject(s) - biology , neurodegeneration , epilepsy , transporter , seizure threshold , neuroscience , audiology , genetics , medicine , gene , disease , anticonvulsant
K‐Cl co‐transporters are encoded by four homologous genes and may have roles in transepithelial transport and in the regulation of cell volume and cytoplasmic chloride. KCC3, an isoform mutated in the human Anderman syndrome, is expressed in brain, epithelia and other tissues. To investigate the physiological functions of KCC3, we disrupted its gene in mice. This severely impaired cell volume regulation as assessed in renal tubules and neurons, and moderately raised intraneuronal Cl − concentration. Kcc3 −/− mice showed severe motor abnormalities correlating with a progressive neurodegeneration in the peripheral and CNS. Although no spontaneous seizures were observed, Kcc3 −/− mice displayed reduced seizure threshold and spike‐wave complexes on electrocorticograms. These resembled EEG abnormalities in patients with Anderman syndrome. Kcc3 −/− mice also displayed arterial hypertension and a slowly progressive deafness. KCC3 was expressed in many, but not all cells of the inner ear K + recycling pathway. These cells slowly degenerated, as did sensory hair cells. The present mouse model has revealed important cellular and systemic functions of KCC3 and is highly relevant for Anderman syndrome.