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Presynaptic Modulation of Synaptic Transmission by Pregnenolone Sulfate as Studied by Optical Recordings

¹International Cooperative Research Project/Solution Oriented Research for Science and Technology Cell Mechanosensing, Japan Science and Technology Agency, Nagoya, Japan; ²Department of Physiology, Nanjing Medical University, Nanjing, China; ³Department of Physiology, Nagoya University Graduate School of Medicine, Nagoya; and ⁴Department of Molecular Physiology, National Institute for Physiological Sciences, Okazaki, Japan

Submitted 4 August 2004; accepted in final form 9 June 2005

The effects of pregnenolone sulfate (PREGS), a putative neurosteroid, on the transmission of perforant path–granule cell synapses were investigated with an optical recording technique in rat hippocampal slices stained with voltage-sensitive dyes. Application of PREGS to the bath solution resulted in an acute augmentation of EPSP in a dose-dependent manner. The PREGS effect was dependent on the extracellular Ca²⁺ concentration ([Ca²⁺]_o), but independent of NMDA receptor activation. PREGS caused a decrease in paired-pulse facilitation, which implies that PREGS positively modulates presynaptic neurotransmitter releases. Firmer support for this mechanism was that PREGS augmented the synaptically induced glial depolarization (SIGD) that reflects the activity of electrogenic glutamate transporters in glial cells during the uptake of released glutamate. The selective 7nAChR antagonist -BGT or MLA prevented the SIGD increase by PREGS. Furthermore DMXB, a selective 7nAChR agonist, mimicked the PREGS effect on SIGD and antagonized the effect of PREGS. The presynaptic effect of PREGS was partially attenuated by the L-type Ca²⁺ channel (VGCC) blocker nifedipine. Based on these findings, we proposed a novel mechanism underlying the facilitated synaptic transmission by PREGS: this neurosteroid sensitizes presynaptic 7nAChR that is followed by an activation of L-type VGCC to increase the presynaptic glutamate release.

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