Abstract
Cerebellar Purkinje neurons (PNs) receive inhibitory GABAergic input from stellate and basket cells, which are located in the outer and inner portions of the molecular layer, respectively. Ethanol (EtOH) was recently shown to increase GABAergic transmission at PNs via a mechanism that involves enhanced calcium release from presynaptic internal stores (J Pharmacol Exp Ther 323:356–364, 2007). Here, we further characterized the effect of EtOH on GABA release and assessed its impact on PN excitability. Using whole-cell patch-clamp electrophysiological techniques in cerebellar vermis parasagittal slices, we found that EtOH acutely increases the frequency but not the amplitude or half-width of miniature and spontaneous inhibitory postsynaptic currents (IPSCs). EtOH significantly increased the amplitude and decreased the paired pulse ratio of IPSCs evoked by stimulation in the outer but not inner molecular layer. In current clamp, EtOH decreased both the amplitude of excitatory postsynaptic potentials evoked in PNs by granule cell axon stimulation and the number of action potentials triggered by these events; these effects depended on GABAA receptor activation because they were not observed in presence of bicuculline. Loose-patch cell-attached PN recordings revealed that neither the spontaneous action potential firing frequency nor the coefficient of variation of the interspike interval was altered by acute EtOH exposure. These findings suggest that EtOH differentially affects GABAergic transmission at stellate cell- and basket cell-to-PN synapses and that it modulates PN firing triggered by granule cell axonal input. These effects could be in part responsible for the cerebellar impairments associated with acute EtOH intoxication.
Footnotes
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This work was supported by National Institutes of Health Grant AA14973.
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M.M. and P.B. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.144865.
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ABBREVIATIONS: EtOH, ethanol; PN, Purkinje neuron; mIPSC, miniature inhibitory postsynaptic current; MLI, molecular layer interneuron; sIPSC, spontaneous inhibitory postsynaptic current; IPSC, inhibitory postsynaptic current; ACSF, artificial cerebrospinal fluid; QX-314, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione; TTX, tetrodotoxin; eIPSC, evoked inhibitory postsynaptic current; K-S, Kolmogorov-Smirnov; NMDA, N-methyl-d-aspartate; AP, action potential.
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↵1 Current affiliation: Department of Basic Neurosciences, University of Geneva, Switzerland.
- Received August 14, 2008.
- Accepted August 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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