ENANTIOSELECTIVE MODULATION OF GABAERGIC SYNAPTIC TRANSMISSION BY STEROIDS AND BENZ[E]INDENES IN HIPPOCAMPAL MICROCULTURES

The effects of enantiomers of the neurosteroid analogues, 3 alpha-hydr oxy-5 alpha-pregnan-20-one (DHP) and 3 alpha-hydroxy-5 alpha-androstan e-17 beta-carbonitrile (ACN), and the benz[e]indene, BI-1, on synaptic currents were examined in microcultures of rat hippocampal neurons. O ver the range of 0.1-10 mu M, the (+)-enantiomers were more potent and effective than their (-)-enantiomeric counterparts in enhancing gamma -aminobutyric acid (GABA)(A) receptor-mediated evoked synaptic current s. The (+)-enantiomers had small effects on peak currents, but slowed the decay of inhibitory synaptic currents, resulting in 2-3-fold incre ases in charge transfer during inhibitory synaptic events at 10 mu M. Similar prolongations of spontaneous miniature inhibitory postsynaptic currents (IPSCs) and responses to brief GABA pulses to outside-out pa tches suggest that the prolongations of evoked synaptic currents resul t primarily from postsynaptic effects. In contrast, the(-)-enantiomers had little effect on evoked IPSCs at concentrations less than or equa l to 1 mu M, but enhanced inhibitory transmission at 10 mu M. At conce ntrations less than or equal to 1 mu M, neither the (+)-nor (-)-enanti omers altered glutamate-mediated excitatory synaptic currents. At 10 m u M, (+)-DHP and (+)-ACN depressed excitatory responses in a bicuculli ne-sensitive fashion, suggesting that direct chloride channel gating b y the steroids contributed to the depression. These data indicate that certain steroids and benz[e]indenes augment inhibitory synaptic trans mission enantioselectively and provide strong support for the hypothes is that steroids act at specific sites on synaptic GABAA receptors rat her than via alteration of membrane lipids. (C) 1998 Wiley-Liss, Inc.