Cytoskeletal changes underlie estrogen's acute effects on synaptic transmission and plasticity.
Cytoskeletal changes underlie estrogen's acute effects on synaptic transmission and plasticity.
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DOI：
10.1523/jneurosci.3059-09.2009
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发表时间：
2009-10-14
期刊：
影响因子：
--
通讯作者：
Lynch G
中科院分区：
文献类型：
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作者：
Kramár EA;Chen LY;Brandon NJ;Rex CS;Liu F;Gall CM;Lynch G
雌激素除了在大脑中的基因组效应外，还引起突触操作的快速和可逆的变化。我们在这里报告，这些急性行动是由于选择性激活的肌动蛋白信号级联反应通常用于生产的长时程增强（LTP）。雌激素，或类固醇的β-受体的选择性激动剂，引起了适度的增加，在快速amatergic传输和一个显着的促进LTP在成年海马切片;这两种效果完全消除latrunculin，一种毒素，防止肌动蛋白丝组装。雌激素也增加了棘浓度的丝状肌动蛋白，并强烈增强其聚合与LTP。对这些作用的起源的研究表明，雌激素激活小的GTdR RhoA并磷酸化（灭活）肌动蛋白切割蛋白cofilin，RhoA的下游靶点。此外，RhoA激酶（ROCK）的拮抗剂阻断雌激素的突触效应。因此，雌激素作为调节亚突触细胞骨架的RhoA>ROCK>LIM激酶>cofilin途径的正调节剂出现。然而，它不会强烈影响第二个LTP相关途径，涉及GTP酶Rac和Cdc 42及其效应p21激活激酶，这可能解释了为什么其急性效应是可逆的。最后，卵巢切除术抑制RhoA活性，脊柱细胞骨架的可塑性，和LTP，而短暂的雌激素注入挽救可塑性，这表明，在可塑性的赤字产生的急性，以及基因组，激素损失的后果。
Estrogen, in addition to its genomic effects in brain, causes rapid and reversible changes to synaptic operations. We report here that these acute actions are due to selective activation of an actin-signaling cascade normally used in the production of long-term potentiation (LTP). Estrogen, or a selective agonist of the steroid’s beta-receptor, caused a modest increase in fast glutamatergic transmission and a pronounced facilitation of LTP in adult hippocampal slices; both effects were completely eliminated by latrunculin, a toxin that prevents actin filament assembly. Estrogen also increased spine concentrations of filamentous actin and strongly enhanced its polymerization in association with LTP. A search for the origins of these effects showed that estrogen activates the small GTPase RhoA and phosphorylates (inactivates) the actin severing protein cofilin, a downstream target of RhoA. Moreover, an antagonist of RhoA kinase (ROCK) blocked estrogen’s synaptic effects. Estrogen thus emerges as a positive modulator of a RhoA>ROCK>LIM kinase>cofilin pathway that regulates the sub-synaptic cytoskeleton. It does not, however, strongly affect a second LTP-related pathway, involving the GTPases Rac and Cdc42 and their effector p21-activated kinase, which may explain why its acute effects are reversible. Finally, ovariectomy depressed RhoA activity, spine cytoskeletal plasticity, and LTP whereas brief infusions of estrogen rescued plasticity, suggesting that the deficits in plasticity arise from acute, as well as genomic, consequences of hormone loss.