title: Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks.
abstract: Estradiol (E2) is locally synthesized within the hippocampus in addition to the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. Molecular mechanisms of modulation through synaptic estrogen receptor (ER) and its downstream signaling, however, have been still unknown. We investigated induction of LTP by the presence of E2 upon weak theta burst stimulation (weak-TBS) in CA1 region of adult male hippocampus. Since only weak-TBS did not induce full-LTP, weak-TBS was sub-threshold stimulation. We observed LTP induction by the presence of E2, after incubation of hippocampal slices with 10nM E2 for 30 min, upon weak-TBS. This E2-induced LTP was blocked by ICI, an ER antagonist. This E2-LTP induction was inhibited by blocking Erk MAPK, PKA, PKC, PI3K, NR2B and CaMKII, individually, suggesting that Erk MAPK, PKA, PKC, PI3K and CaMKII may be involved in downstream signaling for activation of NMDA receptors. Interestingly, dihydrotestosterone suppressed the E2-LTP. We also investigated rapid changes of dendritic spines (=postsynapses) in response to E2, using hippocampal slices from adult male rats. We found 1nM E2 increased the density of spines by approximately 1.3-fold within 2h by imaging Lucifer Yellow-injected CA1 pyramidal neurons. The E2-induced spine increase was blocked by ICI. The increase in spines was suppressed by blocking PI3K, Erk MAPK, p38 MAPK, PKA, PKC, LIMK, CaMKII or calcineurin, individually. On the other hand, blocking JNK did not inhibit the E2-induced spine increase. Taken together, these results suggest that E2 rapidly induced LTP and also increased the spine density through kinase networks that are driven by synaptic ER. This article is part of a Special Issue entitled SI: Brain and Memory.
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan; Bioinformatics Project of Japan Science and Technology Agency, University of Tokyo, Tokyo, Japan; International Collaboration Project (Japan-Taiwan) of Japan Science and Technology Agency, University of Tokyo, Tokyo, Japan; Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hojo
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan.
authors.forename: Muneki
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hotta
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Sato
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Ooishi
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yoshiya
authors.affiliation: International Collaboration Project (Japan-Taiwan) of Japan Science and Technology Agency, University of Tokyo, Tokyo, Japan; Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Bon-Chu
authors.initials: BC
authors.lastname: Chung
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba 3-8-1, Meguro, Tokyo 153, Japan; Bioinformatics Project of Japan Science and Technology Agency, University of Tokyo, Tokyo, Japan; International Collaboration Project (Japan-Taiwan) of Japan Science and Technology Agency, University of Tokyo, Tokyo, Japan; Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan; Project of Special Coordinate Funds for Promoting Science and Technology of Ministry of Education, Science and Technology, University of Tokyo, Tokyo, Japan. Electronic address: kawato@bio.c.u-tokyo.ac.jp.
authors.forename: Suguru
authors.initials: S
authors.lastname: Kawato
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D054461:Lim Kinases / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D020935:MAP Kinase Signaling System; D008297:Male; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D004958:Estradiol; D011494:Protein Kinases; D058539:Phosphatidylinositol 3-Kinase; D054461:Lim Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C
keywords: Estradiol; Estrogen; Estrogen receptor; Kinase; LTP; Rapid action; Spine; Synaptic plasticity