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

descriptionPublicationkeyboard_double_arrow_right Article , Journal 06 Feb 2005 United Kingdom Publisher:Springer Science and Business Media LLCJournal:Nature Neuroscience, volume 8, pages 339-345 (issn: 1097-6256, eissn: 1546-1726,

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

doi: 10.1038/nn1398

pmid: 15696164

pmc: PMC2854077

handle: 1983/4c879871-b097-472d-99f9-d8adf307dcb8

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

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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 GABA(A) receptor (GABAR), alpha6beta3delta, 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 alpha6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of alpha6beta3delta GABARs. Behavioral and electrophysiological comparisons of Gabra6(100R/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.

Country

United Kingdom

Related Organizations

University of Chicago
United States
University of Bristol
United Kingdom
University of California, Los Angeles
United States

Keywords

570, Patch-Clamp Techniques, Genotype, 610, Action Potentials, In Vitro Techniques, Polymorphism, Single Nucleotide, Rats, Sprague-Dawley, Cerebellum, Animals, Drug Interactions, Neurons, Behavior, Animal, Dose-Response Relationship, Drug, Ethanol, Central Nervous System Depressants, Neural Inhibition, Receptors, GABA-A, Rats, Protein Subunits, Animals, Newborn, Psychomotor Performance

1 Research products, page 1 of 1

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