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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Action Potentials / drug effects
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Action Potentials / physiology
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Animals
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Animals, Newborn
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Behavior, Animal
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Central Nervous System Depressants / pharmacology*
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Cerebellum / cytology
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Dose-Response Relationship, Drug
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Drug Interactions
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Ethanol / pharmacology*
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Genotype
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In Vitro Techniques
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Neural Inhibition / drug effects
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Neural Inhibition / physiology*
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Neurons / drug effects
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Neurons / physiology*
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Patch-Clamp Techniques / methods
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Polymorphism, Single Nucleotide / physiology
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Protein Subunits / physiology
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Psychomotor Performance / drug effects
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Psychomotor Performance / physiology*
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Rats
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Rats, Sprague-Dawley
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Receptors, GABA-A / genetics
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Receptors, GABA-A / physiology*
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Transfection / methods
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Xenopus laevis
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gamma-Aminobutyric Acid / pharmacology
Substances
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Central Nervous System Depressants
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Protein Subunits
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Receptors, GABA-A
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Ethanol
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gamma-Aminobutyric Acid