Department of Biological Chemistry, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
J Mol Neurosci. 2010 Jan;40(1-2):47-55. doi: 10.1007/s12031-009-9252-1. Epub 2009 Aug 27.
Mental stress modifies both cholinergic neurotransmission and alternative splicing in the brain, via incompletely understood mechanisms. Here, we report that stress changes brain microRNA (miR) expression and that some of these stress-regulated miRs regulate alternative splicing. Acute and chronic immobilization stress differentially altered the expression of numerous miRs in two stress-responsive regions of the rat brain, the hippocampal CA1 region and the central nucleus of the amygdala. miR-134 and miR-183 levels both increased in the amygdala following acute stress, compared to unstressed controls. Chronic stress decreased miR-134 levels, whereas miR-183 remained unchanged in both the amygdala and CA1. Importantly, miR-134 and miR-183 share a common predicted mRNA target, encoding the splicing factor SC35. Stress was previously shown to upregulate SC35, which promotes the alternative splicing of acetylcholinesterase (AChE) from the synapse-associated isoform AChE-S to the, normally rare, soluble AChE-R protein. Knockdown of miR-183 expression increased SC35 protein levels in vitro, whereas overexpression of miR-183 reduced SC35 protein levels, suggesting a physiological role for miR-183 regulation under stress. We show stress-induced changes in miR-183 and miR-134 and suggest that, by regulating splicing factors and their targets, these changes modify both alternative splicing and cholinergic neurotransmission in the stressed brain.
精神压力通过尚未完全阐明的机制改变大脑中的胆碱能神经递质传递和选择性剪接。在这里，我们报告说压力会改变大脑 microRNA（miR）的表达，并且其中一些受压力调节的 miR 可以调节选择性剪接。急性和慢性束缚应激以不同的方式改变了大鼠大脑两个应激反应区（海马 CA1 区和杏仁核中央核）中众多 miR 的表达。与未受应激的对照组相比，急性应激后杏仁核中 miR-134 和 miR-183 的水平均升高。慢性应激降低了 miR-134 的水平，而 miR-183 在杏仁核和 CA1 中均保持不变。重要的是，miR-134 和 miR-183 共享一个共同的预测 mRNA 靶标，编码剪接因子 SC35。先前的研究表明，应激可上调 SC35，促进乙酰胆碱酯酶（AChE）从突触相关同工型 AChE-S 到通常很少见的可溶性 AChE-R 蛋白的选择性剪接。体外 miR-183 表达的敲低增加了 SC35 蛋白水平，而 miR-183 的过表达降低了 SC35 蛋白水平，这表明 miR-183 在应激下的生理作用。我们展示了应激诱导的 miR-183 和 miR-134 的变化，并表明这些变化通过调节剪接因子及其靶标，改变了应激大脑中的选择性剪接和胆碱能神经递质传递。
