Elsevier

Biochemical Pharmacology

Volume 68, Issue 8, 15 October 2004, Pages 1581-1602
Biochemical Pharmacology

γ-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions

https://doi.org/10.1016/j.bcp.2004.07.023Get rights and content

Abstract

γ-Aminobutyric acid A (GABAA) receptors are believed to mediate a number of alcohol's behavioral actions. Because the subunit composition of GABAA receptors determines receptor pharmacology, behavioral sensitivity to alcohol (ethanol) may depend on which subunits are present (or absent). A number of knock-out and/or transgenic mouse models have been developed (α1, α2, α5, α6, β2, β3, γ2S, γ2L, δ) and tested for behavioral sensitivity to ethanol. Here we review the current GABAA receptor subunit knock-out and transgenic literature for ethanol sensitivity, and integrate these results into those obtained using quantitative trait loci (QTL) analysis and gene expression assays. Converging evidence from these three approaches support the notion that different behavioral actions of ethanol are mediated by specific subunits, and suggest that new drugs that target specific GABAA subunits may selectively alter some behavioral actions of ethanol, without altering others. Current data sets provide strongest evidence for a role of α1-subunits in ethanol-induced loss of righting reflex, and α5-subunits in ethanol-stimulated locomotion. However, three-way validation is hampered by the incomplete behavioral characterization of many of the mutant mice, and additional subunits are likely to be linked to alcohol actions as behavioral testing progresses.

Section snippets

α1-Subunit

The α1-receptor subunit of the GABAA receptor is the most widely distributed α-subunit, having expression in the olfactory bulb, cortex, thalamus, hypothalamus, hippocampus, amygdala, midbrain, and cerebellum [4].

Three different groups have developed mutant mice possessing genetically altered α1-receptor subunits. Rudolph et al. [2] were the first to report knock-in mice possessing a point mutation (H101R) that eliminated diazepam-potentiation of GABA currents in vitro, and a second group

β2-Subunit

β2-Subunits are the most abundant of the beta subunits, and GABAA receptors containing them are found in virtually all brain structures, including olfactory bulb, cortex, hippocampus, thalamus, hypothalamus, amygdala, cerebellum, and midbrain [4]. Given this wide distribution, one would predict that β2-subunits are important for normal GABAergic functioning, and that they may also be important mediators of ethanol's behavioral effects.

β2-Subunit knock-in mice possessing a point mutation

γ2-Subunit knock-out and transgenic mice

The γ2-subunit can be alternatively spliced, creating two different splice variants, the γ2S (short) and γ2L (long). The γ2L splice variant differs from its shorter relative because it posses eight additional amino acids in the third intracellular loop. Importantly, these additional amino acids contain a protein kinase C phosphorylation site, and work by Wafford et al. [54] suggested that these eight amino acids are required for ethanol-enhancement of GABAA receptors possessing the γ2-subunit.

δ-Subunit

δ-Receptor subunits are found in most brain structures, albeit with limited abundance [4]. The δ-subunit is more prevalant in cerebellar granule cells where its localization is almost exclusively extrasynaptic [60]. Interestingly, a recent study suggests that extrasynaptic δ-containing GABAA receptors are particularly sensitive to ethanol [25], [61]. Furthermore, recent work indicates that δ-containing GABAA receptors, especially those also composed of α4 and β, may be up-regulated during

GABAA receptor subunit-associated quantitative trait loci (QTL)

Another way to determine whether different GABAA receptor subunits alter specific ethanol-related behavioral phenotypes is to examine the available quantitative trait loci literature. Ethanol-related behaviors are complex traits. This means that many different genes influence genetic vulnerability to ethanol's behavioral actions. Over the past decade QTL analysis has emerged as a strategy for mapping the many chromosomal regions that contain genes influencing sensitivity to a number of

GABAA receptor subunit-associated gene expression patterns

A genetic difference in DNA sequence within the coding region of an underlying gene is one mechanism by which significant QTLs might influence their associated traits. Such a mechanism might alter the amino acid sequence of the subunit, thereby altering GABAA receptor function and changing behavioral sensitivity to ethanol. For example, a recent report identified a polymorphism in the γ2-subunit gene that predicts a difference in amino acid sequence between the C57BL6/J (B6) and DBA/2J (D2)

Conclusion

GABAA receptors are known to have a role in the modulation of a number of ethanol's behavioral actions. Evidence suggests that the subunit composition of individual GABAA receptors may determine behavioral sensitivity to ethanol [1]. Indeed, studies of subunit knock-out mice have yielded considerable insights into the subunit specificity of ethanol's behavioral actions. These studies complement experiments aimed at mapping chromosomal regions (QTLs) underlying behavioral sensitivity to ethanol.

Acknowledgments

The authors would like to thank Virginia Bleck and Elizabeth Osterndorff-Kahanek for their excellent technical assistance. These experiments were supported by NIAAA (AA07471, AA13520, AA06399, AA14455).

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