Dehydroepiandrosterone sulfate suppresses hippocampal recurrent inhibition and synchronizes neuronal activity to theta rhythm.

Several neurosteroids have proconvulsant and memory-enhancing properties and are potent modulators of the gamma-amino butyric acid (GABA) receptor/chloride-ionophore complex. The effects of in situ microelectrophoretic application of the natural sulfate ester of the neurosteroid dehydroepiandrosterone (DHEAS) on evoked field responses and single-unit activity were evaluated in the dentate gyrus and CA1 hippocampal subfield of halothane-anesthetized rats. The effects of endogenous stimulation of DHEAS by in situ micropressure application of Trilostane ((4 alpha, 5 alpha, 17 beta)-4,5-epoxy-3,17-dihydroxyandrost-2-ene-2- carbonitrile (WIN24540)), an inhibitor of 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), the enzyme that metabolizes DHEAS, on evoked responses and cellular activity in the hippocampus were also investigated. In situ microelectrophoretic application of DHEAS or micropressure application of Trilostane into CA1 markedly increased population excitatory postsynaptic potential (pEPSP) slopes and population spike (PS) amplitudes. Neither DHEAS nor Trilostane altered dentate pEPSP slopes or PS amplitudes, but both increased the amplitude of a late component of the pEPSP. Both DHEAS and Trilostane abolished GABA-mediated paired-pulse inhibition in both the dentate and CA1. In addition, both DHEAS and Trilostane markedly increased the spontaneous firing rate of dentate hilar interneurons (INTs: 256% and 185%), CA1 pyramidal cells (PCs: 95% and 105%), and CA1 oriens/alveus (O/A) interneurons (179% and 85%) and synchronized their firing to hippocampal theta rhythm induced by tail-pinch. These findings indicate that exogenous application and endogenous stimulation of DHEAS modulates hippocampal GABA inhibition in a physiologically relevant manner possibly by entraining hippocampal neurons to theta rhythm.