Production of 5alpha-reduced neurosteroids is developmentally regulated and shapes GABA(A) miniature IPSCs in lamina II of the spinal cord.
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 5alpha-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 5alpha-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 5alpha-reduced neurosteroids.
Keller
A Florence
AF
Laboratoire de Neurophysiologie Cellulaire et Intégrée, Université Louis Pasteur/Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7519, F-67084 Strasbourg, France.
Breton
Jean-Didier
JD
Schlichter
Rémy
R
Poisbeau
Pierrick
P
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000367:Age Factors; D000818:Animals; D003975:Diazepam / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013256:Steroids / Q000378:metabolism*
D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D013256:Steroids; D018120:Finasteride; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D003975:Diazepam; C037850:PK 11195