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Benzodiazepine-induced motor impairment linked to point mutation in cerebeilar GABAA receptor

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Abstract

THE selectively outbred alcohol-non-tolerant (ANT) rat line1 is highly susceptible to impairment of postural reflexes by benzodiazepine agonists2 such as diazepam. ANT cerebella are generally devoid3 of diazepam-insensitive high-affinity binding of the benzodiazepine [3H]Ro 15-4513 (refs 4, 5), whereas in non-selected strains such binding marks a granule-cell-specific GABAA (γ-aminobutyric acid) receptor containing the α6 subunit5,6. A critical determinant for diazepam insensitivity of this ‘wild-type’ cerebeilar GABAA receptor is an arginine residue7 in α6 position 100, where other a subunits carry a histidine8. Here we report that the ct6 gene of ANT rats is expressed at wild-type levels but carries a point mutation generating an arginine-to-glutamine substitution at position 100. In consequence, α6(Q 100)β2γ2 receptors show diazepam-mediated potentiation of GABA-activated currents and diazepam-sensitive binding of [3H]Rol5-4513. Our results suggest that cerebeilar motor control may be a distinct behavioural correlate of the a6-subunit-containing GABAA receptor subtype.

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Authors and Affiliations

  1. Laboratory of Molecular Neuroendocrinology, Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, 6900, Heidelberg, Germany

    Esa R. Korpi & Peter H. Seeburg

  2. Biomedical Research Center, Alko Ltd, PO Box 350, SF-00101, Helsinki, Finland

    Esa R. Korpi

  3. Department of Neurobiology, University of Heidelberg, Im Neuenheimer Feld 345, 6900, Heidelberg, Germany

    Claudia Kleingoor & Helmut Kettenmann

Authors
  1. Esa R. Korpi
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  2. Claudia Kleingoor
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  3. Helmut Kettenmann
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  4. Peter H. Seeburg
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Korpi, E., Kleingoor, C., Kettenmann, H. et al. Benzodiazepine-induced motor impairment linked to point mutation in cerebeilar GABAA receptor. Nature 361, 356–359 (1993). https://doi.org/10.1038/361356a0

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