Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Korpi, E.R. et al.

Korpi, Koikkalainen, Vekovischeva, Mäkelä, Kleinz, Uusi-Oukari, Wisden,

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.[1]

References

Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice. Korpi, E.R., Koikkalainen, P., Vekovischeva, O.Y., Mäkelä, R., Kleinz, R., Uusi-Oukari, M., Wisden, W. Eur. J. Neurosci. (1999) [Pubmed]

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