Production of 5alpha-reduced neurosteroids Is developmentally regulated and shapes GABA(A) miniture IPSCs in lamina II of the spinal cord.
Date
2004
Authors
Keller, Florence A
Breton, Jean-Didier
Schlichter, Remy
Poisbeau, Pierrick
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Society for Neuroscience
Abstract
In lamina II of the spinal dorsal horn, synaptic inhibition mediated by ionotropic GABAA 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 5α-reductase, accelerated the decay kinetics of GABAA 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 5α-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 GABAA mIPSCs in a PK11195- and finasteride-sensitive manner. This condition also increased the proportion of mixed GABAA/glycine mIPSCs in the immature animals and led to the reappearance of mixed GABAA/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 5α-reduced neurosteroids.
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Keywords: 3alpha hydroxy 5alpha pregnan 20 one; 4 aminobutyric acid A receptor; benzodiazepine receptor; benzodiazepine receptor blocking agent; diazepam; finasteride; flumazenil; glycine receptor; n sec butyl 1 (2 chlorophenyl) n methyl 3 isoquinolinecarboxamide; Allopregnanolone; Benzodiazepine; Cotransmission; Dorsal horn; GABA A; Inhibition; mIPSCs; Neurosteroidogenesis; Neurosteroids; Nociception; Pain; Substantia gelatinosa
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Journal of Neuroscience
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Journal article
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2037-12-31
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