Znamensky Vladimir, Akama Keith T, McEwen Bruce S, Milner Teresa A
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Neurosci. 2003 Mar 15;23(6):2340-7. doi: 10.1523/JNEUROSCI.23-06-02340.2003.
In addition to genomic pathways, estrogens may regulate gene expression by activating specific signal transduction pathways, such as that involving phosphatidylinositol 3-kinase (PI3-K) and the subsequent phosphorylation of Akt (protein kinase B). The Akt pathway regulates various cellular events, including the initiation of protein synthesis. Our previous studies showed that synaptogenesis in hippocampal CA1 pyramidal cell dendritic spines is highest when brain estrogen levels are highest. To address the role of Akt in this process, the subcellular distribution of phosphorylated Akt immunoreactivity (pAkt-I) in the hippocampus of female rats across the estrous cycle and male rats was analyzed by light microscopy (LM) and electron microscopy (EM). By LM, the density of pAkt-I in stratum radiatum of CA1 was significantly higher in proestrus rats (or in estrogen-supplemented ovariectomized females) compared with diestrus, estrus, or male rats. By EM, pAkt-I was found throughout the shafts and in select spines of stratum radiatum dendrites. Quantitative ultrastructural analysis identifying pAkt-I with immunogold particles revealed that proestrus rats compared with diestrus, estrus, and male rats contained significantly higher pAkt-I associated with (1) dendritic spines (both cytoplasm and plasmalemma), (2) spine apparati located within 0.1 microm of dendritic spine bases, (3) endoplasmic reticula and polyribosomes in the cytoplasm of dendritic shafts, and (4) the plasmalemma of dendritic shafts. These findings suggest that estrogens may regulate spine formation in CA1 pyramidal neurons via Akt-mediated signaling events.
除了基因组途径外，雌激素还可通过激活特定的信号转导途径来调节基因表达，比如涉及磷脂酰肌醇3激酶（PI3-K）以及随后Akt（蛋白激酶B）磷酸化的途径。Akt途径调节各种细胞活动，包括蛋白质合成的起始。我们之前的研究表明，当脑内雌激素水平最高时，海马CA1锥体细胞树突棘中的突触形成最为活跃。为了探究Akt在此过程中的作用，通过光学显微镜（LM）和电子显微镜（EM）分析了雌性大鼠发情周期各阶段及雄性大鼠海马中磷酸化Akt免疫反应性（pAkt-I）的亚细胞分布。通过光学显微镜观察，与动情间期、发情期大鼠或雄性大鼠相比，动情前期大鼠（或补充雌激素的去卵巢雌性大鼠）CA1辐射层中pAkt-I的密度显著更高。通过电子显微镜观察，在辐射层树突的整个轴突以及部分棘中均发现了pAkt-I。用免疫金颗粒鉴定pAkt-I的定量超微结构分析显示，与动情间期、发情期大鼠和雄性大鼠相比，动情前期大鼠的pAkt-I与以下结构显著相关：（1）树突棘（细胞质和质膜）；（2）位于树突棘基部0.1微米范围内的棘装置；（3）树突轴突细胞质中的内质网和多聚核糖体；（4）树突轴突的质膜。这些发现表明，雌激素可能通过Akt介导的信号事件调节CA1锥体细胞中的棘形成。
