Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice.
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.
Korpi
E R
ER
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. esa.korp@utu.fi
Koikkalainen
P
P
Vekovischeva
O Y
OY
Mäkelä
R
R
Kleinz
R
R
Uusi-Oukari
M
M
Wisden
W
W
D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000503:physiopathology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D018698:Glutamic Acid / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009412:Nerve Fibers / Q000737:chemistry / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects; D011689:Purkinje Cells / Q000737:chemistry* / Q000502:physiology*; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000737:chemistry / Q000502:physiology