Modulation of Hippocampal Synaptic Plasticity by Brain Steroid Hormones

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。我们显示了必需酶(mRNA和蛋白质)在成年雄性大鼠海马区的表达以及神经元/突触定位。质谱分析表明，雌二醇(E_2)、睾酮(T)和双氢睾酮(DHT)的确切水平分别为8 nM、18 nM和7 nM，远高于它们在血浆中的水平。雄性大鼠海马区E_2、T水平高于雌性。肾上腺切除大鼠海马区皮质酮水平为7 nM，通过对成年雄性大鼠海马片棘突发生和长时程增强(LTP)的分析，证实了雌二醇(E_2)对大鼠海马片突触调节和长时程增强(LTP)的快速调节作用。LTP分析显示，1nM雌二醇灌流可完全挽救1μM皮质酮对LTP的抑制作用。突触定位的ER、α和GR参与了这些快速效应。对海马片中单个锥体神经元进行树突棘分析。脊柱密度及其头部直径通过数学和自动化软件SPISO-3D获得，该软件通过计算几何参数来识别脊柱。1 nM时，E_2通过突触ER、α→、PKA和PKC、→、MAPK、→、肌动蛋白聚合、新生的脊椎等途径迅速增加棘突密度。T和DHT也增加了棘突的密度。MAPK、PKA和PKC也参与了这些棘突发生过程。

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.