Mukai Hideo, Kimoto Tetsuya, Hojo Yasushi, Kawato Suguru, Murakami Gen, Higo Shimpei, Hatanaka Yusuke, Ogiue-Ikeda Mari
Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Meguro, Tokyo 153-8902, Japan.
Biochim Biophys Acta. 2010 Oct;1800(10):1030-44. doi: 10.1016/j.bbagen.2009.11.002. Epub 2009 Nov 10.
The hippocampus is a center for learning and memory as well as a target of Alzheimer's disease in aged humans. Synaptic modulation by estrogen is essential to understand the molecular mechanisms of estrogen replacement therapy. Because the local synthesis of estrogen occurs in the hippocampus of both sexes, in addition to the estrogen supply from the gonads, its functions are attracting much attention. Hippocampal estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly. Slow actions of 17ß-estradiol (17ß-E2) occur via classical nuclear receptors (ERα or ERß), while rapid E2 actions occur via synapse-localized ERα or ERß. Elevation or decrease of the E2 concentration changes rapidly the density and morphology of spines in CA1-CA3 neurons. ERα, but not ERß, drives this enhancement/suppression of spinogenesis. Kinase networks are involved downstream of ERα. The long-term depression but not the long-term potentiation is modulated rapidly by changes of E2 level. Determination of the E2 concentration in the hippocampus is enabled by mass-spectrometry in combination with derivatization methods. The E2 level in the hippocampus is as high as approx. 8 nM for the male and 0.5-2 nM for the female, which is much higher than that in circulation. Therefore, hippocampus-derived E2 plays a major role in modulation of synaptic plasticity. Many hippocampal slice experiments measure the restorative effects of E2 by supplementation of E2 to E2-depleted slices. Accordingly, isolated slice experiments can be used as in vitro models of in vivo estrogen replacement therapy for ovariectomized female animals with depleted circulating estrogen.
海马体是学习和记忆的中心，也是老年人类患阿尔茨海默病的靶点。雌激素对突触的调节作用对于理解雌激素替代疗法的分子机制至关重要。由于雌激素的局部合成不仅发生在两性的性腺中，也发生在海马体中，因此其功能备受关注。海马体雌激素不仅能缓慢调节与记忆相关的突触可塑性，还能快速调节。17β-雌二醇（17β-E2）的缓慢作用是通过经典核受体（ERα或ERβ）介导的，而E2的快速作用则是通过突触定位的ERα或ERβ介导的。E2浓度的升高或降低会迅速改变CA1-CA3神经元中棘突的密度和形态。驱动这种棘突生成增强/抑制的是ERα，而非ERβ。激酶网络参与ERα的下游作用。E2水平的变化能快速调节长时程抑制，而非长时程增强。通过质谱结合衍生化方法能够测定海马体中的E2浓度。海马体中的E2水平，男性约为8 nM，女性为0.5 - 2 nM，远高于循环中的水平。因此，海马体衍生的E2在突触可塑性调节中起主要作用。许多海马体切片实验通过向E2耗尽的切片补充E2来测量E2的恢复作用。相应地，分离切片实验可作为体内雌激素替代疗法的体外模型，用于循环雌激素耗尽的去卵巢雌性动物。
