Variation in cerebellar sensitivity to alcohol/ethanol (EtOH) is a heritable trait associated with alcohol use disorder (AUD) in humans and high EtOH consumption in rodents, but the underlying mechanisms are poorly understood. A recently identified cellular substrate of cerebellar sensitivity to EtOH: the GABAergic system of cerebellar granule cells (GCs), shows divergent responses to EtOH paralleling EtOH consumption and motor impairment phenotype. Although GCs are the dominant afferent integrator in the cerebellum, such integration is shared by unipolar brush cells (UBCs) in vestibulocerebellar lobes. UBCs receive both GABAergic and glycinergic inhibition, both of which may mediate diverse neurological effects of EtOH. Therefore, the impact of recreational concentrations of EtOH (~10-50mM) on GABAAR- and glycine receptor (GlyR)-mediated spontaneous inhibitory postsynaptic currents (sIPSC) of UBCs in cerebellar slices were characterized. Sprague Dawley rat (SDR) UBCs exhibited sIPSCs mediated by GABAARs, GlyRs or both, and EtOH dose dependently (10, 26, 52mM) increased their frequency and amplitude. EtOH increased the frequency of glycinergic and GABAergic sIPSCs, and selectively enhanced the amplitude of glycinergic sIPSCs. This GlyR-specific enhancement of sIPSC amplitude resulted from EtOH actions at presynaptic Golgi cells and via protein kinase C-dependent direct actions on postsynaptic GlyRs. The magnitude of EtOH-induced increases in UBC sIPSC activity varied across SDRs and two lines of mice, in parallel with their respective alcohol consumption/motor impairment phenotypes. These data indicate that Golgi cell to UBC inhibitory synapses are targets of EtOH, which acts at pre- and postsynaptic sites, via Golgi cell excitation and direct GlyR enhancement.
- unipolar brush cell
- Copyright © 2016, Journal of Neurophysiology