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ORIGINAL ARTICLE

Developmental Regulation of -Carboline-Induced Inhibition of Glycine-Evoked Responses Depends on Glycine Receptor Subunit Expression

Center for Cellular and Molecular Neuroscience (J.-M.M., L.N., C.G., G.H., B.R., S.B., G.M., J.-M.R.) and Department of Neurology (B.R., S.B., G.M.), University of Liège, Liège, Belgium; Unité Mixte Recherche 7102, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, Paris, France (J.-M.M., P.L.); Division of Molecular Neurobiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, England (L.N.); and Department of Physiology, Transnationale Universiteit Limburg/Limburgs Universitair Centrum, Diepenbeek, Belgium (J.-M.R.)

Abstract

In this work, we show that -carbolines, which are known negative allosteric modulators of GABA_A receptors, inhibit glycine-induced currents of embryonic mouse spinal cord and hippocampal neurons. In both cell types, -carboline-induced inhibition of glycine receptor (GlyR)-mediated responses decreases with time in culture. Single-channel recordings show that the major conductance levels of GlyR unitary currents shifts from high levels (50 pS) in 2 to 3 days in vitro (DIV) neurons to low levels (<50 pS) in 11 to 14 DIV neurons, assessing the replacement of functional homomeric GlyR by heteromeric GlyR. In cultured spinal cord neurons, the disappearance of -carboline inhibition of glycine responses and high conductance levels is almost complete in mature neurons, whereas a weaker decrease in -carboline-evoked glycine response inhibition and high conductance level proportion is observed in hippocampal neurons. To confirm the hypothesis that the decreased sensitivity of GlyR to -carbolines depends on subunit expression, Chinese hamster ovary cells were permanently transfected either with GlyR 2 subunit alone or in combination with GlyR subunit. Single-channel recordings revealed that the major conductance levels shifted from high levels (50 pS) in GlyR-2-transfected cells to low levels (<50 pS) in GlyR-2+-containing cells. Consistently, both picrotoxin- and -carboline-induced inhibition of glycine-gated currents were significantly decreased in GlyR-2+-transfected cells compared with GlyR-2-containing cells. In summary, we demonstrate that the incorporation of subunits in GlyRs confers resistance not only to picrotoxin but also to -carboline-induced inhibition. Furthermore, we also provide evidence that hippocampal neurons undergo in vitro a partial maturation process of their GlyR-mediated responses.

Address correspondence to: Dr. Jean-Michel Rigo, Department of Physiology, Transnationale Universiteit Limburg/Limburgs Universitair Centrum, Biomedisch Onderzoekinstituut, B-3590 Diepenbeek, Belgium. E-mail: jeanmichel.rigo{at}luc.ac.be

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