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Cerebellar granule‐cell‐specific GABA A receptors attenuate benzodiazepine‐induced ataxia: evidence from α6‐subunit‐deficient mice
Author(s) -
Korpi Esa R.,
Koikkalainen Paula,
Vekovischeva Olga Y.,
Mäkelä Riikka,
Kleinz Raymonde,
UusiOukari Mikko,
Wisden William
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00421.x
Subject(s) - cerebellum , gabaa receptor , flumazenil , ataxia , benzodiazepine , neuroscience , receptor , granule cell , chemistry , pharmacology , medicine , biology , endocrinology , hippocampal formation , dentate gyrus
Benzodiazepine‐ and alcohol‐induced ataxias in rodents have been proposed to be affected by the γ‐aminobutyric acid type A (GABA A ) receptor α6 subunit, which contributes to receptors specifically expressed in cerebellar granule cells. We have studied an α6 –/– 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 α6 –/– and α6 +/+ mice. On the rotarod test, however, the mutant mice were significantly more impaired by diazepam (5–20 mg/kg, i.p.), when compared with α6 +/+ control and background C57BL/6J and 129/SvJ mouse lines. Ethanol (2.0–2.5 g/kg, i.p.) produced similar impairment in the α6 –/– and α6 +/+ mice. Diazepam‐induced ataxia in α6 –/– mice could be reversed by the benzodiazepine site antagonist flumazenil, indicating the involvement of the remaining α1β2/3γ2 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 α6 subunit‐dependent actions in the cerebellar cortex can be compensated by other receptor subtypes; but if not for the α6 subunit, patients on benzodiazepine medication would suffer considerably from ataxic side‐effects.