Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice

Eur J Neurosci. 1999 Jan;11(1):233-40. doi: 10.1046/j.1460-9568.1999.00421.x.


Benzodiazepine- and alcohol-induced ataxias in rodents have been proposed to be affected by the gamma-aminobutyric acid type A (GABAA) 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 GABAA receptors of the granule cells. The level of activity in this synapse is crucial in regulating the execution of motor tasks. We conclude that GABAA 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia / chemically induced
  • Ataxia / physiopathology*
  • Benzodiazepines / pharmacology*
  • Central Nervous System Depressants / pharmacology
  • Diazepam / pharmacology
  • Ethanol / pharmacology
  • GABA Modulators / pharmacology
  • GABA-A Receptor Agonists
  • Glutamic Acid / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / physiology
  • Nerve Fibers / chemistry
  • Nerve Fibers / physiology
  • Psychomotor Performance / drug effects
  • Purkinje Cells / chemistry*
  • Purkinje Cells / physiology*
  • Receptors, GABA-A / genetics*
  • Receptors, GABA-A / metabolism
  • Synapses / chemistry
  • Synapses / physiology


  • Central Nervous System Depressants
  • GABA Modulators
  • GABA-A Receptor Agonists
  • Receptors, GABA-A
  • Benzodiazepines
  • Ethanol
  • Glutamic Acid
  • Diazepam