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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.
Brickley,
Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance.
2001, Pubmed
Brickley,
Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance.
2001,
Pubmed
Campos,
Expression of GABA(A) receptor subunits in rat brainstem auditory pathways: cochlear nuclei, superior olivary complex and nucleus of the lateral lemniscus.
2001,
Pubmed
Carta,
Alcohol enhances GABAergic transmission to cerebellar granule cells via an increase in Golgi cell excitability.
2004,
Pubmed
Chadderton,
Integration of quanta in cerebellar granule cells during sensory processing.
2004,
Pubmed
Choi,
The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference.
2004,
Pubmed
Davies,
A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans.
2003,
Pubmed
Farrant,
GABA receptors, granule cells and genes.
1993,
Pubmed
Hodge,
Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon.
1999,
Pubmed
Homanics,
Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics.
1997,
Pubmed
Homanics,
Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.
1997,
Pubmed
Jones,
Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression.
1997,
Pubmed
Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed
Kaneda,
Whole-cell and single-channel currents activated by GABA and glycine in granule cells of the rat cerebellum.
1995,
Pubmed
Kobayashi,
Ethanol opens G-protein-activated inwardly rectifying K+ channels.
1999,
Pubmed
,
Xenbase
Korpi,
Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor.
1993,
Pubmed
Korpi,
Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice.
1999,
Pubmed
Korpi,
Cerebellar GABAA receptors in two rat lines selected for high and low sensitivity to moderate alcohol doses: pharmacological and genetic studies.
1992,
Pubmed
Lewohl,
G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action.
1999,
Pubmed
,
Xenbase
Lovinger,
Ethanol inhibits NMDA-activated ion current in hippocampal neurons.
1989,
Pubmed
Löw,
Molecular and neuronal substrate for the selective attenuation of anxiety.
2000,
Pubmed
Macdonald,
GABAA receptor channels.
1994,
Pubmed
McKernan,
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.
2000,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Mitchell,
Shunting inhibition modulates neuronal gain during synaptic excitation.
2003,
Pubmed
Möhler,
GABA(A)-receptor subtypes: a new pharmacology.
2001,
Pubmed
Nusser,
Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells.
2002,
Pubmed
Nusser,
Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene.
1999,
Pubmed
Nusser,
Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells.
1998,
Pubmed
Overstreet,
Paradoxical reduction of synaptic inhibition by vigabatrin.
2001,
Pubmed
Peng,
GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain.
2002,
Pubmed
Pirker,
GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.
2000,
Pubmed
Pöltl,
Subunit composition and quantitative importance of GABA(A) receptor subtypes in the cerebellum of mouse and rat.
2003,
Pubmed
Radcliffe,
Behavioral characterization of alcohol-tolerant and alcohol-nontolerant rat lines and an f(2) generation.
2004,
Pubmed
Rossi,
Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry.
1998,
Pubmed
Rudolph,
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
1999,
Pubmed
Saba,
The R100Q mutation of the GABA(A) alpha(6) receptor subunit may contribute to voluntary aversion to ethanol in the sNP rat line.
2001,
Pubmed
,
Xenbase
Saxena,
Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms.
1996,
Pubmed
Semyanov,
GABA uptake regulates cortical excitability via cell type-specific tonic inhibition.
2003,
Pubmed
Semyanov,
Tonically active GABA A receptors: modulating gain and maintaining the tone.
2004,
Pubmed
Stell,
Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors.
2003,
Pubmed
Sundstrom-Poromaa,
Hormonally regulated alpha(4)beta(2)delta GABA(A) receptors are a target for alcohol.
2002,
Pubmed
,
Xenbase
Suzdak,
A selective imidazobenzodiazepine antagonist of ethanol in the rat.
1986,
Pubmed
Uusi-Oukari,
Long-range interactions in neuronal gene expression: evidence from gene targeting in the GABA(A) receptor beta2-alpha6-alpha1-gamma2 subunit gene cluster.
2000,
Pubmed
Vallee,
Alcohol in the western world.
1998,
Pubmed
Vekovischeva,
Cerebellar GABA(A) receptors and anxiolytic action of diazepam.
1999,
Pubmed
Wallner,
Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans.
2003,
Pubmed
,
Xenbase
Wei,
Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons.
2004,
Pubmed
Wisden,
The cerebellum: a model system for studying GABAA receptor diversity.
1996,
Pubmed
