Developmentally Regulated and Shapes GABAA Miniature IPSCs in Lamina II of the Spinal Cord

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 GABAA 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 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 5 -reduced neurosteroids in young rats that confers slow decay kinetics to GABAA mIPSCs. At all of the ages, selective stimulation of PBR by diazepam in the presence of flumazenil prolonged GABAA mIPSCs in a PK11195and 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 5 -reduced neurosteroids.