title: Chronic DHEAS administration facilitates hippocampal long-term potentiation via an amplification of Src-dependent NMDA receptor signaling.
abstract: Dehydroepiandrosterone 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.
authors.affiliation: Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. lingchen@njmu.edu.cn
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Kishio
authors.initials: K
authors.lastname: Furuya
authors.forename: Xiao-Niu
authors.initials: XN
authors.lastname: Dai
authors.forename: Nozomu
authors.initials: N
authors.lastname: Mori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sokabe
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage*; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D019314:Dehydroepiandrosterone Sulfate; D016392:Proto-Oncogene Proteins pp60(c-src); D002118:Calcium