ArticleModulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies
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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Synaptic targets: Chronic alcohol actions
2017, NeuropharmacologyCitation Excerpt :These findings remain inconsistent, and have not been uniformly replicated across all studies on EtOH/GABAARs in heterologous systems (reviewed in (Aguayo et al., 2002; Forstera et al., 2016; Lovinger and Homanics, 2007; Lovinger and Roberto, 2013)). Acute EtOH potentiation of extrasynaptic tonic current has been observed in recordings from the cerebellum, hippocampus, accumbens, amygdala and thalamus (Botta et al., 2007; Chandra et al., 2006; Forstera et al., 2016; Glykys et al., 2007; Hanchar et al., 2005; Herman et al., 2013; Jia et al., 2008; Liang et al., 2014; Pirker et al., 2000; Valenzuela and Jotty, 2015; Wei et al., 2004). Chronic ethanol exposure induces many neuroadaptations within GABAergic synapses in a brain region-specific manner.
Ethanol attenuates sensory stimulus-evoked responses in cerebellar granule cells via activation of GABA<inf>A</inf> receptors in vivo in mice
2014, Neuroscience LettersCitation Excerpt :Indeed, our results showed that cerebellar surface perfusion of GABAA receptor antagonist, Gabazine induced an increase in amplitude of GCs sensory responses (unpublished data), indicated that tonic inhibition of GCs by the GABAergic system diminishes transfer of sensory information. Consistent with previous studies in living animals [16] and cerebellar slices [17,30,31], we here found that cerebellar surface perfusion of ethanol inhibited GCs sensory responses in a dose-dependent manner. The ethanol-induced inhibition of GCs sensory responses were blocked by GABAA receptor antagonist, indicating that ethanol inhibits mossy fiber-mediated excitation via GABAA receptors.
- 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.