Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

H. Jacob Hanchar, Paul D. Dodson, Richard W. Olsen, Thomas S. Otis, Martin Wallner*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

238 Citations (Scopus)

Abstract

Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABAA receptor (GABAR), α6β3δ, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in α6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of α6β3δ GABARs. Behavioral and electrophysiological comparisons of Gabra6100R/100R and Gabra6 100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.

Original languageEnglish
Pages (from-to)339-345
Number of pages7
JournalNature Neuroscience
Volume8
Issue number3
DOIs
Publication statusPublished - 1 Mar 2005

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