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The Journal of Neuroscience, March 26, 2008, 28(13):3427-3437; doi:10.1523/JNEUROSCI.5076-07.2008

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Cellular/Molecular
Regional Differences in the Decay Kinetics of GABA_A Receptor-Mediated Miniature IPSCs in the Dorsal Horn of the Rat Spinal Cord Are Determined by Mitochondrial Transport of Cholesterol

Perrine Inquimbert, Jean-Luc Rodeau, and Rémy Schlichter

Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université Louis Pasteur, F-67084 Strasbourg, France

Correspondence should be addressed to Prof. Rémy Schlichter, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université Louis Pasteur, 21 rue René Descartes, F-67084 Strasbourg, France. Email: schlichter{at}neurochem.u-strasbg.fr

We examined the possibility of a differential spatial control in the endogenous production of 35-reduced steroids and its consequences on GABA_A receptor-mediated miniature IPSCs (mIPSCs) in laminas II and III–IV of the rat spinal cord dorsal horn (DH). Early in postnatal development [younger than postnatal day 8 (P8)], mIPSCs displayed slow decay kinetics in laminas II and III–IV resulting from a continuous local production of 35-reduced steroids. This was mediated by the tonic activity of the translocator protein of 18 kDa (TSPO), which controls neurosteroid synthesis by regulating the transport of cholesterol across the mitochondrial membrane system. TSPO activity disappeared in laminas III–IV after P8 and was functionally downregulated in lamina II after P15, resulting in a marked reduction of mIPSC duration in these laminas. TSPO-mediated synthesis of 35-reduced steroids was spatially restricted, because, at P9–P15, when their production was maximal in lamina II, no sign of spillover to laminas III–IV was apparent. Interestingly, after P8, the enzymes necessary for the synthesis of 35-reduced steroids remained functional in laminas III–IV and could produce such steroids from various precursors or after a single subcutaneous injection of progesterone. Moreover, induction of an acute peripheral inflammation by intraplantar injection of carrageenan, restored a maximal TSPO-mediated neurosteroidogenesis in laminas III–IV. Our results indicate that the decay kinetics of GABA_A receptor-mediated mIPSCs in the DH of the spinal cord are primarily controlled by 35-reduced steroids, which can be produced from circulating steroid precursors and/or in a spatially restricted manner by the modulation of the activity of TSPO.

Key words: peripheral benzodiazepine receptor; synaptic transmission; synaptic inhibition; somatosensory; inflammation; neurosteroid

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Received June 13, 2007; revised Feb. 14, 2008; accepted Feb. 20, 2008.

Correspondence should be addressed to Prof. Rémy Schlichter, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université Louis Pasteur, 21 rue René Descartes, F-67084 Strasbourg, France. Email: schlichter{at}neurochem.u-strasbg.fr

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