title: Na+/K+-ATPase inhibition partially mimics the ethanol-induced increase of the Golgi cell-dependent component of the tonic GABAergic current in rat cerebellar granule cells.
abstract: Cerebellar granule cells (CGNs) are one of many neurons that express phasic and tonic GABAergic conductances. Although it is well established that Golgi cells (GoCs) mediate phasic GABAergic currents in CGNs, their role in mediating tonic currents in CGNs (CGN-I(tonic)) is controversial. Earlier studies suggested that GoCs mediate a component of CGN-I(tonic) that is present only in preparations from immature rodents. However, more recent studies have detected a GoC-dependent component of CGN-I(tonic) in preparations of mature rodents. In addition, acute exposure to ethanol was shown to potentiate the GoC component of CGN-I(tonic) and to induce a parallel increase in spontaneous inhibitory postsynaptic current frequency at CGNs. Here, we tested the hypothesis that these effects of ethanol on GABAergic transmission in CGNs are mediated by inhibition of the Na(+)/K(+)-ATPase. We used whole-cell patch-clamp electrophysiology techniques in cerebellar slices of male rats (postnatal day 23-30). Under these conditions, we reliably detected a GoC-dependent component of CGN-I(tonic) that could be blocked with tetrodotoxin. Further analysis revealed a positive correlation between basal sIPSC frequency and the magnitude of the GoC-dependent component of CGN-I(tonic). Inhibition of the Na(+)/K(+)-ATPase with a submaximal concentration of ouabain partially mimicked the ethanol-induced potentiation of both phasic and tonic GABAergic currents in CGNs. Modeling studies suggest that selective inhibition of the Na(+)/K(+)-ATPase in GoCs can, in part, explain these effects of ethanol. These findings establish a novel mechanism of action of ethanol on GABAergic transmission in the central nervous system.
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors: Marvin R
authors: MR
authors: Diaz
authors: Aya
authors: A
authors: Wadleigh
authors: Shyam
authors: S
authors: Kumar
authors: Erik
authors: E
authors: De Schutter
authors: C Fernando
authors: CF
authors: Valenzuela
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D003198:Computer Simulation; D000431:Ethanol / Q000494:pharmacology*; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008959:Models, Neurological; D010042:Ouabain / Q000494:pharmacology*; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase
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