Enantioselective modulation of GABAergic synaptic transmission by steroids and benz[e]indenes in hippocampal microcultures
✍ Scribed by Charles F. Zorumski; Steven J. Mennerick; Douglas F. Covey
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 172 KB
- Volume
- 29
- Category
- Article
- ISSN
- 0887-4476
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✦ Synopsis
The effects of enantiomers of the neurosteroid analogues, 3␣-hydroxy-5␣pregnan-20-one (DHP) and 3␣-hydroxy-5␣-androstane-17-carbonitrile (ACN), and the benz[e]indene, BI-1, on synaptic currents were examined in microcultures of rat hippocampal neurons. Over the range of 0.1-10 µM, the (ϩ)-enantiomers were more potent and effective than their (Ϫ)-enantiomeric counterparts in enhancing ␥-aminobutyric acid (GABA) A receptor-mediated evoked synaptic currents. The (ϩ)-enantiomers had small effects on peak currents, but slowed the decay of inhibitory synaptic currents, resulting in 2-3-fold increases in charge transfer during inhibitory synaptic events at 10 µM. Similar prolongations of spontaneous miniature inhibitory postsynaptic currents (IPSCs) and responses to brief GABA pulses to outside-out patches suggest that the prolongations of evoked synaptic currents result primarily from postsynaptic effects. In contrast, the (Ϫ)-enantiomers had little effect on evoked IPSCs at concentrations Յ1 µM, but enhanced inhibitory transmission at 10 µM. At concentrations Յ1 µM, neither the (ϩ)-nor (Ϫ)-enantiomers altered glutamate-mediated excitatory synaptic currents. At 10 µM, (ϩ)-DHP and (ϩ)-ACN depressed excitatory responses in a bicuculline-sensitive fashion, suggesting that direct chloride channel gating by the steroids contributed to the depression. These data indicate that certain steroids and benz[e]indenes augment inhibitory synaptic transmission enantioselectively and provide strong support for the hypothesis that steroids act at specific sites on synaptic GABA A receptors rather than via alteration of membrane lipids.