Alcohol Suppresses Tonic GABAA Receptor Currents in Cerebellar Granule Cells in the Prairie Vole: A Neural Signature of High‐Alcohol‐Consuming Genotypes. (18th July 2016) - Kaplan, Joshua S.
Abstract : Background: Evidence indicates that the cerebellum plays a role in genetic predilection to excessive alcohol (ethanol [EtOH]) consumption in rodents and humans, but the molecular mechanisms mediating such predilection are not understood. We recently determined that EtOH has opposite actions (enhancement or suppression) on tonic GABAA receptor (GABAA R) currents in cerebellar granule cells (GCs) in low‐ and high‐EtOH‐consuming rodents, respectively, and proposed that variation in GC tonic GABAA R current responses to EtOH contributes to genetic variation in EtOH consumption phenotype. Methods: Voltage‐clamp recordings of GCs in acutely prepared slices of cerebellum were used to evaluate the effect of EtOH on GC tonic GABAA R currents in another high‐EtOH‐consuming rodent, prairie voles (PVs). Results: EtOH (52 mM) suppressed the magnitude of the tonic GABAA R current in 57% of cells, had no effect in 38% of cells, and enhanced the tonic GABAA R current in 5% of cells. This result is similar to GCs from high‐EtOH‐consuming C57BL/6J (B6) mice, but it differs from the enhancement of tonic GABAA R currents by EtOH in low‐EtOH‐consuming DBA/2J (D2) mice and Sprague Dawley (SD) rats. EtOH suppression of tonic GABAA R currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABAA R‐mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABAA Rs, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase (nNOS; which can mediate EtOH enhancement of GABA release) demonstrated that nNOS expression in the GC layer of PV cerebellum was similar to the levels seen in B6 mice, both being significantly reduced relative to D2 mice and SD rats. Conclusions: Combined, these data highlight the GC GABAA R response to EtOH in another species, the high‐EtOH‐consuming PV, which correlates with EtOH consumption phenotype and further implicates the GC GABAA R system as a contributing mechanism to high EtOH consumption. Abstract : Insensitivity to EtOH‐induced disruption of cerebellar processing is a risk factor for excessive alcohol consumption in rodents and humans. We report that GABAergic inhibition of cerebellar granule cells shows opposite responses to EtOH (suppression versus enhancement) in high and low EtOH consuming rodent genotypes (prairie voles/C57BL/6J mice versus Sprague‐Dawley rats/DBA/2J mice) respectively. The opposite response to EtOH is due to differential expression of nNOS, the inhibition of which underlies EtOH enhancement of GABAergic transmission in low EtOH consuming genotypes.