Rapid modulation of synaptic plasticity by estrogens as well as endocrine disrupters in hippocampal neurons

Mari Ogiue-Ikeda, Nobuaki Tanabe, Hideo Mukai, Yasushi Hojo, Gen Murakami, Tomokazu Tsurugizawa, Norio Takata, Tetsuya Kimoto, Suguru Kawato

Research output: Contribution to journalReview articlepeer-review

104 Citations (Scopus)


Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. However, molecular mechanisms of the rapid action are yet largely unknown. We here describe rapid modulation of representative synaptic plasticity, i.e., long-term depression (LTD), long-term potentiation (LTP) and spinogenesis, by 17beta-estradiol, selective estrogen agonists as well as endocrine disrupters. The authors demonstrated that 1-10 nM estradiol induced rapid enhancement of LTD within 1 h in not only CA1 but also CA3 and dentate gyrus (DG). On the other hand, the modulation of LTP by estradiol was not statistically significant. The total density of spines was increased in CA1 pyramidal neurons, within 2 h after application of estradiol. The total density of thorns (postsynaptic spine-like structure) was, however, decreased by estradiol in CA3 pyramidal neurons. Both the increase of spines in CA1 and the decrease of thorns in CA3 were completely suppressed by Erk MAP kinase inhibitor. Only ERalpha agonist PPT induced the same enhancement/suppression effect as estradiol on both LTD and spinogenesis in CA1 and CA3. ERbeta agonist DPN induced completely different results. ERalpha localized in spines and presynapses of principal glutamatergic neurons in CA1, CA3 and DG. The same ERalpha was also located in nuclei and cytoplasm. Identification of ERalpha was successfully performed using purified RC-19 antibody. Non-purified ERalpha antisera, however, reacted significantly with unknown proteins, resulting in wrong immunostaining different from real ERalpha distribution. An issue of 'endocrine disrupters' (1-100 nM low dose of environmental chemicals), which are artificial xenoestrogenic or anti-xenoestrogenic substances, has emerged as a social and environmental problem. Endocrine disrupters were found to significantly modulate LTD and spinogenesis. Bisphenol A (BPA) and diethylstilbestrol (DES) enhanced LTD in CA1 and CA3. The total spine density was significantly increased by BPA and DES in CA1. Most probable receptors for BPA and DES may be Ralpha; however, other receptors might also be involved.

Original languageEnglish
Pages (from-to)363-375
Number of pages13
JournalBrain Research Reviews
Issue number2
Publication statusPublished - 2008 Mar 14
Externally publishedYes


  • Bisphenol A
  • Endocrine disrupter
  • Estradiol
  • Estrogen receptor
  • Hippocampus
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology


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