Rapid modulation of long-term depression and spinogenesis via synaptic estrogen receptors in hippocampal principal neurons

Hideo Mukai, Tomokazu Tsurugizawa, Gen Murakami, Shiro Kominami, Hirotaka Ishii, Mari Ogiue-Ikeda, Norio Takata, Nobuaki Tanabe, Aizo Furukawa, Yasushi Hojo, Yuuki Ooishi, John Morrison, William G.M. Janssen, John A. Rose, Pierre Chambon, Shigeaki Kato, Shunsuke Izumi, Takeshi Yamazaki, Tetsuya Kimoto, Suguru Kawato

Research output: Contribution to journalArticlepeer-review

159 Scopus citations


Rapid modulation of hippocampal synaptic plasticity by estrogen has long been a hot topic, but analysis of molecular mechanisms via synaptic estrogen receptors has been seriously difficult. Here, two types of independent synaptic plasticity, long-term depression (LTD) and spinogenesis, were investigated, in response to 17β-estradiol and agonists of estrogen receptors using hippocampal slices from adult male rats. Multi-electrode investigations demonstrated that estradiol rapidly enhanced LTD not only in CA1 but also in CA3 and dentate gyrus. Dendritic spine morphology analysis demonstrated that the density of thin type spines was selectively increased in CA1 pyramidal neurons within 2 h after application of 1 nm estradiol. This enhancement of spinogenesis was completely suppressed by mitogen-activated protein (MAP) kinase inhibitor. Only the estrogen receptor (ER) alpha agonist, (propyl-pyrazole-trinyl)tris- phenol (PPT), induced the same enhancing effect as estradiol on both LTD and spinogenesis in the CA1. The ERbeta agonist, (4-hydroxyphenyl)-propionitrile (DPN), suppressed LTD and did not affect spinogenesis. Because the mode of synaptic modulations by estradiol was mostly the same as that by the ERalpha agonist, a search was made for synaptic ERalpha using purified RC-19 antibody qualified using ERalpha knockout (KO) mice. Localization of ERalpha in spines of principal glutamatergic neurons was demonstrated using immunogold electron microscopy and immunohistochemistry. ERalpha was also located in nuclei, cytoplasm and presynapses.

Original languageEnglish (US)
Pages (from-to)950-967
Number of pages18
JournalJournal of Neurochemistry
Issue number4
StatePublished - Feb 1 2007
Externally publishedYes


  • Estrogen
  • Estrogen receptor
  • Hippocampus
  • Neurosteroid
  • Spine
  • Synaptic plasticity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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