Benzodiazepine- and alcohol-induced ataxias in rodents have been
proposed to be affected by the gamma-aminobutyric acid type A (GABA_A)
receptor alpha 6 subunit, which contributes to receptors specifically
expressed in cerebellar granule cells. We have studied an alpha 6 -/-
mouse line for motor performance and drug sensitivity. These mice, as a
result of a specific genetic lesion, carry a precise impairment at their
Golgi-granule cell synapses. On motor performance tests (rotarod,
horizontal wire, pole descending, staircase and swimming tests) there
were no robust baseline differences in motor function or motor learning
between alpha 6 -/- and alpha 6 +/+ mice. On the rotarod test, however,
the mutant mice were significantly more impaired by diazepam (5-20
mg/kg, i.p.), when compared with alpha 6 +/+ control and background
C57BL/6J and 129/SvJ mouse lines. Ethanol (2.0-2.5 g/kg, i.p.) produced
similar impairment in the alpha 6 -/- and alpha +/+ mice.
Diazepam-induced ataxia in alpha 6 -/- mice could be reversed by the
benzodiazepine site antagonist flumazenil, indicating the involvement of
the remaining alpha 1 beta 2/3 gamma 2 GABA_A receptors of the granule
cells. The level of activity in this synapse is crucial in regulating
the execution of motor tasks. We conclude that GABA_A receptor alpha 6
subunit-dependent actions in the cerebellar cortex can be compensated by
other receptor subtypes; but if not for the alpha 6 subunit, patients
on benzodiazepine medication would suffer considerably from ataxic
side-effects.