Elsevier

Alcohol

Volume 41, Issue 3, May 2007, Pages 187-199
Alcohol

Article
Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies

https://doi.org/10.1016/j.alcohol.2007.04.004Get rights and content

Abstract

Cerebellar granule neurons (CGNs) receive inhibitory input from Golgi cells in the form of phasic and tonic currents that are mediated by postsynaptic and extrasynaptic γ-aminobutyric acid type A (GABAA) receptors, respectively. Extrasynaptic receptors are thought to contain α6βxδ subunits. Here, we review studies on ethanol (EtOH) modulation of these receptors, which have yielded contradictory results. Although studies with recombinant receptors expressed in Xenopus oocytes indicate that α6β3δ receptors are potently enhanced by acute exposure to low (≥3 mM) EtOH concentrations, this effect was not observed when these receptors were expressed in Chinese hamster ovary cells. Slice recordings of CGNs have consistently shown that EtOH increases the frequency of phasic spontaneous inhibitory postsynaptic currents (sIPSCs), as well as the tonic current amplitude and noise. However, there is a lack of consensus as to whether EtOH directly acts on extrasynaptic receptors or modulates them indirectly; that is, via an increase in spillover of synaptically released GABA. It was recently demonstrated that an R to Q mutation of amino acid 100 of the α6 subunit increases the effect of EtOH on both sIPSCs and tonic current. These electrophysiological findings have not been reproducible in our hands. Moreover, it was shown the α6-R100Q mutation enhances sensitivity to the motor-impairing effects of EtOH in outbred Sprague-Dawley rats, but this was not observed in a line of rats selectively bred for high sensitivity to EtOH-induced motor alterations (Alcohol Non-Tolerant rats). We conclude that currently there is insufficient evidence conclusively supporting a direct potentiation of extrasynaptic GABAA receptors following acute EtOH exposure in CGNs.

Section snippets

The cerebellum as a target of ethanol

The cerebellum is involved in the control of balance as well as the coordination, planning, and fine regulation of voluntary movement. In addition, this brain region has been shown to be important for certain cognitive functions, including thought, behavior, and emotion (Schmahmann and Sherman, 1997). The cerebellum is composed of the cerebellar cortex, inner white matter, and deep cerebellar nuclei. Neurons of the cerebellar cortex are organized into three layers. The outermost is the

Overview of GABAergic input to CGNs

CGNs relay excitatory input from mossy fibers to Purkinje neurons via divergent pathways and this process is profoundly modulated by GABAergic transmission. Golgi interneurons provide two types of GABAergic input to CGNs: tonic and phasic. Tonic GABAergic inhibition dominates over phasic inhibition (Hamann et al., 2002). The presence of a tonic GABAergic current in granule cells was first demonstrated by the existence of a bicuculline sensitive “background noise current” that persisted in the

α6-R100Q and EtOH-related behaviors in the AT and ANT selected lines

AT and ANT rats were selectively bred for differential ataxic sensitivity to EtOH as measured by performance on the tilting plane test (Eriksson and Rusi, 1981; see Korpi et al., this issue). In this test, each animal was given three trials in which it was placed on the raised end of a mechanical tilting plane that was elevated from a flat horizontal position to an 84° angle in 5 s. The average angle at which the animal slid to the base of the plane was recorded (baseline) followed by an

Studies with outbred Sprague-Dawley rats

A significant effect of the α6-R100Q mutation on EtOH-mediated impairment on the accelerating rotarod was observed in a population of outbred Sprague-Dawley rats, which was recently found to carry both the R and Q alleles (Hanchar et al., 2005). This would appear to be at odds with the lack of such an effect on the tilting plane test and other behaviors in the AT and ANT rats, as described above. The authors suggested that the behavioral effect of the mutation is operative only at lower EtOH

Conclusions and future directions

EtOH is a difficult drug to study experimentally in part because it has multiple targets and its actions are dependent on a myriad of factors, including intracellular signaling pathways (Lovinger and Crabbe, 2005, Ron and Jurd, 2005). Moreover, EtOH is a solvent that can cause contaminants to be released from tubing, glassware, and other items used in laboratory experiments (Machu et al., 1998, Tully et al., 2000). Therefore, interpretations of EtOH research data are inherently complex and

Acknowledgments

This study was supported by NIH grants R01 AA14973 (to C.F.V.), R01 AA13177 (to R.A.R.), and R01 AA12650 (to R.A.D.). We are grateful to Don Partridge for critically reading the manuscript.

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    1

    Present address: Department of Experimental Biology, University of Cagliari, Italy.

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    Present address: Department of Basic Neurosciences, University of Geneva, Switzerland.

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