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Modulation of Hippocampal Synaptic Plasticity by Brain Steroid Hormones

脑类固醇激素对海马突触可塑性的调节

基本信息

批准号：
21370064
负责人：
KAWATO Suguru
金额：
$ 12.48万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

We have demonstrated(1) hippocampal synthesis of estrogen, androgen, corticosterone, and(2) rapid synaptic modulation by these brain steroids.<Synthesis> We showed expression as well as neuronal/synaptic localization of essential enzymes(mRNA and protein) in the adult male rat hippocampus. Mass-spectrometric analysis demonstrated that exact levels of estradiol(E2), testosterone(T), dihydrotestosterone(DHT) were 8 nM, 18 nM and 7 nM, respectively, which were much higher than their levels in plasma. Male hippocampal levels of E2, and T were higher than those of female. Corticosterone level was 7 nM which was determined in the hippocampus of adrenalectomized rats.<Synaptic Modulation> Estradiol(E2)-induced rapid modulation(within 2 h) was demonstrated by analysis of spinogenesis and long-term potentiation(LTP) of adult male rat hippocampal slices. LTP analysis showed that 1 nM estradiol perfusion completely rescued the 1μM corticosterone-induced suppression of LTP. Synaptically localized ERαand GR are involved in these rapid effects. Analysis of dendritic spines was performed for single pyramidal neurons in the hippocampal slices. The density of spines and their head diameters were obtained by mathematical and automated software Spiso-3D which identifies spines by calculating geometrical parameters. E2 at 1 nM rapidly increased the density of spines via pathways of synaptic ERα→PKA and PKC→MAPK→actin polymerization→new spine. Both T and DHT also increased the density of spines. MAPK, PKA and PKC were also involved in these spinogenesis processes.

我们已经证明了（1）海马合成雌激素、雄激素、皮质酮，以及（2）这些脑类固醇对突触的快速调节。<Synthesis>我们显示了成年雄性大鼠海马中必需酶（mRNA和蛋白质）的表达以及神经元/突触定位。质谱分析表明，雌二醇（E2），睾酮（T），双氢睾酮（DHT）的精确水平分别为8 nM，18 nM和7 nM，这远远高于其在血浆中的水平。男性海马E2、T水平高于女性。肾上腺切除大鼠海马中测定的皮质酮水平为7 nM。<Synaptic Modulation>通过分析成年雄性大鼠海马脑片的棘突形成和长时程增强（LTP），证明了雌二醇（E2）诱导的快速调制（2小时内）。LTP分析表明，1 nM雌二醇灌注完全挽救了1μM皮质酮诱导的LTP抑制。突触定位的ERα和GR参与这些快速效应。对海马切片中单个锥体神经元进行树突棘分析。通过数学和自动化软件Spiso-3D获得棘的密度及其头部直径，该软件通过计算几何参数来识别棘。1 nM E2通过ERα→PKA和PKC→MAPK→肌动蛋白聚合→新棘的突触通路迅速增加棘的密度。T和DHT也增加了棘的密度。MAPK、PKA和PKC也参与了这些棘发生过程。