Zhou Rulun, Yuan Peixiong, Wang Yun, Hunsberger Joshua G, Elkahloun Abdel, Wei Yanling, Damschroder-Williams Patricia, Du Jing, Chen Guang, Manji Husseini K
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropsychopharmacology. 2009 May;34(6):1395-405. doi: 10.1038/npp.2008.131. Epub 2008 Aug 13.
MicroRNAs (miRNAs) regulate messenger RNA (mRNA) translation in a sequence-specific manner and are emerging as critical regulators of central nervous system plasticity. We found hippocampal miRNA level changes following chronic treatment with mood stabilizers (lithium and valproate (VPA)). Several of these miRNAs were then confirmed by quantitative PCR: let-7b, let-7c, miR-128a, miR-24a, miR-30c, miR-34a, miR-221, and miR-144. The predicted effectors of these miRNAs are involved in neurite outgrowth, neurogenesis, and signaling of PTEN, ERK, and Wnt/beta-catenin pathways. Interestingly, several of these effector-coding genes are also genetic risk candidates for bipolar disorder. We provide evidence that treatment with mood stabilizers increases these potential susceptibility genes in vivo: dipeptidyl-peptidase 10, metabotropic glutamate receptor 7 (GRM7), and thyroid hormone receptor, beta. Treatment of primary cultures with lithium- or VPA-lowered levels of miR-34a and elevated levels of GRM7, a predicted effector of miR-34a. Conversely, miR-34a precursor treatment lowered GRM7 levels and treatment with a miR-34a inhibitor enhanced GRM7 levels. These data confirm that endogenous miR-34a regulates GRM7 levels and supports the notion that miR-34a contributes to the effects of lithium and VPA on GRM7. These findings are the first to demonstrate that miRNAs and their predicted effectors are targets for the action of psychotherapeutic drugs.
微小RNA（miRNA）以序列特异性方式调节信使RNA（mRNA）翻译，正逐渐成为中枢神经系统可塑性的关键调节因子。我们发现，在长期使用心境稳定剂（锂盐和丙戊酸盐（VPA））治疗后，海马体中的miRNA水平发生了变化。随后通过定量PCR证实了其中几种miRNA：let-7b、let-7c、miR-128a、miR-24a、miR-30c、miR-34a、miR-221和miR-144。这些miRNA的预测效应分子参与神经突生长、神经发生以及PTEN、ERK和Wnt/β-连环蛋白信号通路。有趣的是，这些效应分子编码基因中的几个也是双相情感障碍的遗传风险候选基因。我们提供的证据表明，心境稳定剂治疗可在体内增加这些潜在的易感基因：二肽基肽酶10、代谢型谷氨酸受体7（GRM7）和甲状腺激素受体β。用锂盐或VPA处理原代培养物可降低miR-34a的水平并提高GRM7的水平，GRM7是miR-34a的预测效应分子。相反，miR-34a前体处理可降低GRM7水平，而用miR-34a抑制剂处理则可提高GRM7水平。这些数据证实内源性miR-34a调节GRM7水平，并支持miR-34a促成锂盐和VPA对GRM7作用的观点。这些发现首次证明miRNA及其预测的效应分子是心理治疗药物作用的靶点。
