Neurosteroid paradoxical enhancement of paired-pulse inhibition through paired-pulse facilitation of inhibitory circuits in dentate granule cells Michael J. Thomas a , Manuel Mameli a , Mario Carta a , C. Fernando Valenzuela a , Pui-Kai Li b , L. Donald Partridge a, ) a Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA b Division of Medical Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA Received 8 August 2004; received in revised form 8 October 2004; accepted 27 November 2004 Abstract Neurosteroids are produced in the brain independently of peripheral endocrine glands to act locally in the nervous system. They exert potent promnesic effects and play significant roles in mental health-related disorders. In part, neurosteroids act by affecting ligand-gated ion channels and metabotropic receptors through rapid non-genomic processes. We have previously demonstrated that neurosteroids also affect synaptic transmission presynaptically in the CA1 region of the hippocampus. Here we describe the effects of the most abundant neurosteroid in the rodent brain, pregnenolone sulfate (PregS), on signal processing in the dentate subfield of the hippocampus. We show that PregS acts presynaptically at low concentrations (300 nM) to enhance paired-pulse facilitation (PPF) in perforant pathway terminals on dentate granule cells. Similar effects were found with two steroid sulfatase inhibitors demonstrating a potential contribution of endogenous steroids to dentate synaptic plasticity. This enhanced presynaptic facilitation paradoxically increases paired-pulse inhibition (PPI) at short interpulse intervals. Based on these data, a model of dentate gyrus circuit interactions is proposed for the presynaptic action of PregS on the filtering dynamics of the dentate subfield at frequencies similar to those of the endogenous signals from the entorhinal cortex. These modeling studies are consistent with experimental measurements demonstrating positive modulation by PregS at low frequencies and negative modulation at high frequencies. These studies show an important role for the presynaptic action of neurosteroids in modulating input signals to the hippocampus. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Dentate gyrus; Hippocampal slice; Recurrent inhibition 1. Introduction Neurosteroids, produced locally in neurons and glial cells, are important modulators of neuronal function (Baulieu, 1998). Pregnenolone sulfate (PregS), the most common neurosteroid in rodent brain (Corpechot et al., 1983), is produced by a steroid sulfotransferase from pregnenolone and is converted back to pregnenolone by a steroid sulfatase. It is well established that this and other neurosteroids have promnesic and cognitive- enhancing roles within the neocortex (Barrett-Connor and Edelstein, 1994; Flood et al., 1992, 1999; Darnaudery et al., 2000; Akwa et al., 2001; Matthews et al., 2002). Increases in brain levels of neurosteroids have been tied to improvements in memory acquisition and retention including increased performance in the Morris Water Test in rats (Darnaudery et al., 2000; Johnson et al., 2000) and there is a correlation of circulating neuro- steroid levels with cognitive performance in humans ) Corresponding author. Tel.: C1 505 272 8815; fax: C1 505 272 8082. E-mail addresses: kavabilo@yahoo.com (M.J. Thomas), dpartridge@ salud.unm.edu (L.D. Partridge). 0028-3908/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2004.11.014 ARTICLE IN PRESS DTD 5 Neuropharmacology -- (2005) ---–--- www.elsevier.com/locate/neuropharm