There is substantial heritable risk for developing alcohol dependence. One established risk factor associated with enhanced alcohol consumption is a behavioral insensitivity to alcohol-induced impairment on a cerebellar- dependent measure, such as body sway. However, the cellular mechanisms underlying this behavioral insensitivity are poorly understood. One potential site of differential alcohol action that contributes to this behavioral phenotype is on tonic GABAA receptor (GABAAR)-mediated transmission of cerebellar granule cells (GCs) which powerfully regulates the transmission of afferent information from the periphery through the cerebellar cortex. Previous research in low-alcohol consuming Sprague-Dawley (SD) rats identified that alcohol enhances the magnitude of tonic GABAAR inhibition of GCs, which may impair behavior by dampening transmission through the cerebellar cortex. In my preliminary experiments, I investigated whether the alcohol- induced enhancement of tonic GABAAR inhibition of GCs differed across rodents with divergent sensitivities to alcohol-induced cerebellar ataxia and alcohol consumption phenotypes. I found that in DBA/2J (D2) mice, which like SD rats, express a behaviorally sensitive and low-alcohol consuming phenotype, alcohol greatly enhanced tonic GABAAR inhibition of GCs. However, intriguingly, alcohol suppressed tonic GABAAR inhibition in C57BL/6J (B6) mice, which more closely model the human cerebellar low LR phenotype. These experiments illuminated a potentially significant role that alcohol action on tonic GABAAR inhibition of GCs plays in alcohol- induced ataxia and alcohol intake. The research goals of the current application are to determine if genotypic differences in alcohol-induced modulation of tonic GABAAR-mediated inhibition of GCs differentially impacts signal transmission through the cerebellar cortex and establish its relationship to cerebellar ataxia and EtOH consumption. The broad overall hypothesis is that the suppressive actions of alcohol on tonic GABAAR currents in B6 mouse GCs is less disruptive (compared to enhancement observed in D2 mice and SD rats) of transmission through the cerebellar cortex, and thus is less disruptive of cerebellar dependent behaviors. In particular, I propose that the novel suppressive action of EtOH on GC tonic GABAAR currents contributes to the B6's reduced sensitivity to EtOH-induced motor impairment, which in turn contributes to their high EtOH consumption phenotype. I will test these hypotheses with pharmacological and electrophysiological studies of GC tonic GABAAR modulation of signal transmission through the cerebellar cortex (Aim 1) and behavioral studies designed to determine how manipulations of tonic GABAAR currents impacts cerebellar-dependent rotarod performance and EtOH intake (Aim 2). The information gained from this proposal will add substantially to our understanding of the cellular correlates that underlie a known behavioral risk factor for developing an alcohol use disorder and can be applied to the development of novel pharmacological interventions to combat this destructive condition.
Pharmacological treatments for combating alcohol use disorders have limited effectiveness due to an incomplete understanding of the mechanisms by which alcohol's action at the cellular level impact behavior. This project will improve our understanding of how alcohol's effect on tonic GABAA receptor-mediated inhibition of cerebellar granule cells impacts cerebellar output and contributes to alcohol-induced cerebellar impairment and alcohol intake. Information gained can be applied toward the development of effective pharmacological treatment strategies to limit the destructive social and economic burden of alcohol use disorders.
|Kaplan, Josh Steven; Nipper, Michelle A; Richardson, Ben D et al. (2016) Pharmacologically Counteracting a Phenotypic Difference in Cerebellar GABAA Receptor Response to Alcohol Prevents Excessive Alcohol Consumption in a High Alcohol-Consuming Rodent Genotype. J Neurosci 36:9019-25|
|Kaplan, Joshua S; Mohr, Claudia; Hostetler, Caroline M et al. (2016) Alcohol Suppresses Tonic GABAA Receptor Currents in Cerebellar Granule Cells in the Prairie Vole: A Neural Signature of High-Alcohol-Consuming Genotypes. Alcohol Clin Exp Res 40:1617-26|
|Kaplan, Joshua S; Mohr, Claudia; Rossi, David J (2013) Opposite actions of alcohol on tonic GABA(A) receptor currents mediated by nNOS and PKC activity. Nat Neurosci 16:1783-93|
|Mohr, Claudia; Kolotushkina, Olena; Kaplan, Joshua S et al. (2013) Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype. Front Neural Circuits 7:189|