• Ling Chen, Yoshiaki Miyamoto, Kishio Furuya, Xiao-Niu Dai, Nozomu Mori, and Masahiro Sokabe.
• Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. lingchen@njmu.edu.cn
• Neuropharmacology. 2006 Sep 1;51(3):659-70.

AbstractDehydroepiandrosterone sulfate (DHEAS) has well characterized effects on memory and cognitive performances. Recently we have reported that repetitive administration of DHEAS lowers the threshold pulse number in inducing activity-dependent long-term potentiation (LTP) in rat hippocampal Schaffer collateral-CA1 synapses, in which a sub-threshold high frequency stimulation (HFS, 30 pulses at 100 Hz) for normal rats could induce robust LTP in DHEAS-treated rats (Chen et al., 2006). Here we report that the sub-threshold HFS could trigger the phosphorylation of Src and ERK2 in the DHEAS-treated rats, but not in control rats. We found in slices obtained from the DHEAS-treated rats that NMDA-induced intracellular Ca2+([Ca2+]i) transients in CA1 pyramidal neurons were significantly potentiated, which was essential for the Src and ERK2 phosphorylations. The activation of ERK2, a downstream factor of Src family kinase, was required for the DHEAS-facilitated LTP. The Src family kinase inhibitor PP2, but not its inactive homologue PP3, attenuated the NMDA-induced [Ca2+]i increase and abolished the DHEAS-facilitated LTP. These findings suggest that the chronic administration of DHEAS brings the NMDA receptor (NMDAr) to a potentiated state that causes an enough level of [Ca2+]i increase for LTP induction even by the sub-threshold HFS. The potentiated [Ca2+]i transient by the sub-threshold HFS may trigger the Src phosphorylation that will further potentiate NMDAr followed by an activation of ERK2 and LTP induction. This novel postsynaptic NMDAr/Src-mediated signal amplification through "NMDAr-Ca2+-->Src-->NMDAr-Ca2+" cycle may play a pivotal role in the DHEAS-facilitated LTP induction.

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