Local production of estrogen and its rapid modulatory action on synaptic plasticity

Abstract

It has long been a common sense that sex hormones are synthesized in the gonads, and reach the brain via the blood circulation. In contrast with this view, the authors demonstrate that estrogen and androgen are also synthesized locally in the hippocampus of adult animals, from cholesterol through dehydroepiandrosterone in hippocampal neurons. These neurosteroids are synthesized by cytochrome P450s and hydroxysteroid dehydrogenases and 5α-reductase. The expression levels of enzymes are as low as 1/200-1/50,000 of those in endocrine organs, preventing quantitative investigations. Localization of P450(17α) and P450arom is observed in synapses of principal glutamatergic neurons, in addition to endoplasmic reticulum, suggesting synaptocrine machanisms. Because several nanomolar estrogen and androgen are observed in the hippocampus, they are expected to have physiological functions. Estrogen modulates memory-related synaptic plasticity not only slowly, but also rapidly in the hippocampus. Molecular mechanisms of rapid action via membrane receptors have not been well elucidated in comparison with those of delayed action via genomic processes. We here describe rapid modulation of representative synaptic plasticity, i.e., long-term depression (LTD), long-term potentiation (LTP) and spinogenesis, by 17β-estradiol, selective estrogen agonists. We demonstrate that 1-10 nM estradiol induced rapid enhancement of LTD within 1 h in CA1, CA3 and dentate gyrus (DG). On the other hand, the modulation of LTP by estradiol is not statistically significant. The total density of spines is increased in CA1 pyramidal neurons, within 2 h after application of estradiol. The total density of thorns (postsynaptic spine-like structure) is, however, decreased by estradiol in CA3 pyramidal neurons. Both the increase of spines in CA1 and the decrease of thorns in CA3 are driven by Erk MAP kinase. Only agonist of estrogen receptor ERalpha induces the same enhancement/suppression effect as estradiol on both LTD and spinogenesis in CA1 and CA3. ERbeta agonist induces completely different results. Estrogen receptor ERalpha localizes in spines and presynapses of principal glutamatergic neurons in CA1, CA3 and DG. The same ERalpha is also located in nuclei. Identification of ERalpha is successfully performed using purified RC-19 antibody. Attention must be paid to the fact that non-purified ERalpha antisera often react significantly with unknown proteins, resulting in wrong staining different from real ERalpha distribution. Identification of kinases/phosphatases in downstream of ERalpha as well as other synaptic estrogen receptors is essential to advance the field. © 2008 Springer Netherlands.