Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABA(A) receptor desensitization

We examined the effects of the neurosteroid pregnenolone sulfate (PS) on GABA(A) receptor-mediated synaptic currents and currents elicited by rapid applications of GABA onto nucleated outside-out patches in cultured postnatal rat hippocampal neurons. At 10 μM, PS significantly depressed peak responses and accelerated the decay of evoked inhibitory synaptic currents. In nucleated outside-out patches, PS depressed peak currents and speeded deactivation after 5 msec applications of a saturating concentration of GABA. PS also increased the rate and degree of macroscopic GABA receptor desensitization during prolonged GABA applications. In a paired GABA application paradigm, PS slowed the rate of recovery from desensitization. In contrast to its prominent effects on currents produced by saturating GABA concentrations, PS had only small effects on peak currents and failed to alter deactivation after brief applications of the weakly desensitizing GABA(A) receptor agonists taurine and β-alanine. However, when β-alanine was applied for a sufficient duration to promote receptor desensitization, PS augmented macroscopic desensitization and slowed deactivation. These results suggest that PS inhibits GABA-gated chloride currents by enhancing receptor desensitization and stabilizing desensitized states. This contention is supported by kinetic modeling studies in which increases in the rate of entry into doubly liganded desensitized states mimic most effects of PS.