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The Journal of Neuroscience, January 28, 2004, 24(4):907-915; doi:10.1523/JNEUROSCI.4642-03.2004

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Cellular/Molecular
Production of 5-Reduced Neurosteroids Is Developmentally Regulated and Shapes GABA_A Miniature IPSCs in Lamina II of the Spinal Cord

A. Florence Keller, Jean-Didier Breton, Rémy Schlichter, and Pierrick Poisbeau

Laboratoire de Neurophysiologie Cellulaire et Intégrée, Université Louis Pasteur/Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7519, F-67084 Strasbourg, France

In lamina II of the spinal dorsal horn, synaptic inhibition mediated by ionotropic GABA_A and glycine receptors contributes to the integration of peripheral nociceptive messages. Whole-cell patch-clamp recordings were performed from lamina II neurons in spinal cord slices to study the properties of miniature IPSCs (mIPSCs) mediated by activation of GABA_A and glycine receptors in immature (<30 d) and adult rats. Blockade of neurosteroidogenesis by 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK11195), an inhibitor of the peripheral benzodiazepine receptor (PBR), or finasteride, which blocks 5-reductase, accelerated the decay kinetics of GABA_A receptor-mediated mIPSCs in immature, but not in adult animals. Glycine receptor-mediated mIPSCs remained unaffected under these conditions. These results suggest the presence of a tonic production of 5-reduced neurosteroids in young rats that confers slow decay kinetics to GABA_A mIPSCs. At all of the ages, selective stimulation of PBR by diazepam in the presence of flumazenil prolonged GABA_A mIPSCs in a PK11195- and finasteride-sensitive manner. This condition also increased the proportion of mixed GABA_A/glycine mIPSCs in the immature animals and led to the reappearance of mixed GABA_A/glycine mIPSCs in the adult. Our results might point to an original mechanism by which the strength of synaptic inhibition can be adjusted locally in the CNS during development and under physiological and/or pathological conditions by controlling the synthesis of endogenous 5-reduced neurosteroids.

Key words: pain; nociception; neurosteroids; inhibition; cotransmission; mIPSCs; GABA_A; substantia gelatinosa; dorsal horn; benzodiazepine; neurosteroidogenesis; allopregnanolone

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Received Aug 13, 2003; revised November 18, 2003; accepted November 20, 2003.

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