Dehydroepiandrosterone sulfate and estrone sulfate reduce GABA-recurrent inhibition in the hippocampus via muscarinic acetylcholine receptors

Several recent studies have established a role for estrogens in ameliorating specific neurodegenerative disorders, mainly those associated with the cholinergic neurons of the basal forebrain and their targets in the cortex and hippocampus. We have previously demonstrated that endogenous and exogenous application of the neurosteroid dehydroepiandrosterone sulfate (DHEAS) markedly reduces GABA-mediated recurrent inhibition and synchronizes hippocampal unit activity to theta rhythm (Steffensen (1995) Hippocampus 5:320-328). In this study, we evaluated the role of muscarinic receptors in mediating the effects of DHEAS and estrone sulfate (ES), the principal circulating estrogen in humans, on short-latency-evoked potential responses, paired-pulse inhibition (PPI), paired-pulse facilitation, and GABA interneuron activity in the dentate gyrus and CA1 subfields of the rat hippocampus. In situ microelectrophoretic application of the muscarinic M2 subtype cholinergic receptor agonist cis-dioxolane, DHEAS, and ES markedly reduced PPI in the dentate and CA1 that was blocked by the M2 receptor antagonist gallamine. Similar to DHEAS, microelectrophoretic administration of ES increased population spike amplitudes, without increasing excitatory transmission, but this effect was not blocked by gallamine. Microelectrophoretic application of cis-dioxolane and ES markedly increased the firing rate of dentate hilar interneurons and CA1 oriens/alveus interneurons and enhanced their synchrony to hippocampal theta rhythm. These findings suggest that select GABA-modulating neurosteroids and neuroactive estrogen sulfates alter septohippocampal cholinergic modulation of hippocampal GABAergic interneurons mediating recurrent, but not feedforward, inhibition of hippocampal principal cell activity.