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

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), 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 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.Humans have been consuming alcohol for thousands of years, and the use of alcoholic beverages pervades human culture and society and can have substantial health effects 1 . Different mechanisms by which ethanol might depress brain function have been proposed based on ethanol's ability to modulate a wide variety of ion channels 2-4 , neurotransmitter receptors 5-10 and transporters 11 . Among these diverse targets, however, GABARs are arguably the most attractive candidates. This is in part because other classes of known GABAR modulators such as benzodiazepines, barbiturates and certain anesthetics lead to behavioral effects that closely resemble ethanol intoxication. Yet despite strong evidence implicating GABARs in ethanol's action, critical details remain unclear. For instance, although it is known that native GABARs are heteropentamers assembled from 19 possible subunits 12,13 , it has not been possible to link the activity of particular GABAR subunits to changes in behavioral sensitivity to ethanol.Recent studies suggest that specific combinations of GABAR subunits (those containing α4β3δ and α6β3δ) are uniquely sensitive to ethanol, showing dose dependencies that mirror blood alcohol levels associated with intoxication in humans 9,10 . GABARs containing α4 and δ subunits are expressed in many brain regions 14,15 , but α6 is found in only two types of neurons (cerebellar granule cells and granule cells in the cochlear nucleus) and is expressed together with δ only in cerebellar granule cells 14,16,17 . In granule cells α6 and δ combine with β subunits Correspondence should be addressed to M.W. (mwallner@mednet.ucla.edu) or T.S.O. (otist@ucla.edu). 3 These authors contributed equally to this work. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We set out to examine whether such extrasynaptic GABARs containing α6 and δ subunits account for behavioral effects of ethanol at moderately intoxicating doses. To link these particular GABARs to behavioral sensitivity, we first characterized a naturally occurring single-nucleotide polymo...

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

“…The δ-GABA A Rs, sometimes called the "one-glass-of-wine" receptors (24), are located in several brain regions, including the thalamus, cerebellum, hippocampus, and striatum (25,26), and show high sensitivity to relatively low doses of ethanol (2)(3)(4)(5)(6)(7)(8)27). A number of previous studies demonstrate the involvement of δ-GABA A Rs in a range of ethanolinduced functional effects, including ataxia, sedation, and reward (2-8).…”

“…The δ-GABA A Rs also represent one of the major targets of ethanol in the CNS, particularly at relatively low ethanol concentrations, and mediate some of the rewarding and ataxic effects of ethanol (2)(3)(4)(5)(6)(7)(8). For instance, a genetic polymorphism that exaggerates the actions of ethanol at δ-GABA A Rs also potentiates ethanolinduced motor impairment (2).…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…However, the complexity of this interpretation is exemplified by the recent observation that GABA responses from the GABA A receptor on granule cells in the cerebellum, which are thought to contain a 6 b X d subunits (Hamann et al, 2002), were not affected by ethanol (Carta et al, 2004). However, Hanchar et al (2005) recently published data that a variant of the GABA A receptor [a 6 (R100)b 3 d] on cerebellar granule cells was more sensitive to ethanol than the native receptor. The basis of this apparent conflict concerning the effect of ethanol on this receptor subtype on the cerebellar granule neurons requires further investigation (see discussion by Carta et al, 2004).…”

Extrasynaptic GABAA receptors in the crosshairs of hormones and ethanol

“…Consistent with the common involvement of the δ subunit-containing GABA A Rs in ovariancycle related anxiety and in mediating the effects of ethanol, women with PMS have increase their alcohol consumption during the luteal phase ( (Charette et al 1990) (Mcleod et al 1994) (Tobin et al 1994), which may be an indication of self-medication since the function of δ subunit-containing GABAARs ((Sundstrom-Poromaa et al 2002;Wallner et al 2003) and the tonic inhibition mediated by them ( (Wei et al 2004;Hanchar et al 2005) are enhanced by sobriety-impairing concentrations of ethanol.…”