BENZODIAZEPINE-INDUCED MOTOR IMPAIRMENT LINKED TO POINT MUTATION IN CEREBELLAR GABA(A) RECEPTOR

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 [H-3]Ro15-4513 (refs 4, 5), whereas in non-selected strains such binding marks a granule-cell-specific GABA(A) (gamma-aminobutyric acid) receptor containing the alpha6 subunit5,6. A critical determinant for diazepam insensitivity of this 'wild-type' cerebellar GABA(A) receptor is an arginine residue7 in alpha6 position 100, where other alpha subunits carry a histidine8. Here we report that the alpha6 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, alpha6(Q100)beta2gamma2 receptors show diazepam-mediated potentiation of GABA-activated currents and diazepam-sensitive binding of [H-3]Ro15-4513. Our results suggest that cerebellar motor control may be a distinct behavioural correlate of the alpha6-subunit-containing GABA(A) receptor subtype.