Bipolar disorder (BP) is a complex psychiatric condition characterized by severe fluctuations in mood for which underlying pathological mechanisms remain unclear. Family and twin studies have identified a hereditary component to the disorder, but a single causative gene (or set of genes) has not been identified. MicroRNAs (miRNAs) are small, noncoding RNAs ∼20 nucleotides in length, that are responsible for the posttranslational regulation of multiple genes. They have been shown to play important roles in neural development as well as in the adult brain, and several miRNAs have been reported to be dysregulated in postmortem brain tissue isolated from bipolar patients. Because there are no viable cellular models to study BP, we have taken advantage of the recent discovery that somatic cells can be reprogrammed to pluripotency then directed to form the full complement of neural cells. Analysis of RNAs extracted from Control and BP patient-derived neurons identified 58 miRNAs that were differentially expressed between the two groups. Using quantitative polymerase chain reaction we validated six miRNAs that were elevated and two miRNAs that were expressed at lower levels in BP-derived neurons. Analysis of the targets of the miRNAs indicate that they may regulate a number of cellular pathways, including axon guidance, Mapk, Ras, Hippo, Neurotrophin, and Wnt signaling. Many are involved in processes previously implicated in BP, such as cell migration, axon guidance, dendrite and synapse development, and function. We have validated targets of several different miRNAs, including AXIN2, BDNF, RELN, and ANK3 as direct targets of differentially expressed miRNAs using luciferase assays. Identification of pathways altered in patient-derived neurons suggests that disruption of these regulatory networks that may contribute to the complex phenotypes in BP.

中文翻译：

---

双相情感障碍患者诱导多能干细胞衍生神经元中的 MicroRNA 改变：参与神经元分化、轴突引导和可塑性的途径。

双相情感障碍（BP）是一种复杂的精神疾病，其特征是情绪严重波动，其潜在的病理机制仍不清楚。家庭和双胞胎研究已经确定了这种疾病的遗传因素，但尚未确定单个致病基因（或一组基因）。MicroRNA (miRNA) 是长度约为 20 个核苷酸的小型非编码 RNA，负责多个基因的翻译后调节。它们已被证明在神经发育以及成人大脑中发挥着重要作用，并且据报道，从双相情感障碍患者死后脑组织中分离出几种 miRNA 失调。由于没有可行的细胞模型来研究血压，我们利用了最近的发现，即体细胞可以被重新编程为多能性，然后被引导形成完整的神经细胞。对从对照和 BP 患者来源的神经元中提取的 RNA 进行分析，发现了 58 个 miRNA 在两组之间表达存在差异。使用定量聚合酶链反应，我们验证了 BP 衍生神经元中表达水平升高的 6 个 miRNA 和表达水平较低的 2 个 miRNA。对 miRNA 靶标的分析表明，它们可能调节许多细胞通路，包括轴突引导、Mapk、Ras、Hippo、神经营养蛋白和 Wnt 信号传导。许多参与先前与 BP 相关的过程，例如细胞迁移、轴突引导、树突和突触发育以及功能。我们使用荧光素酶测定验证了几种不同 miRNA 的靶标，包括AXIN2、BDNF、RELN和ANK3作为差异表达 miRNA 的直接靶标。对患者源性神经元中改变的通路的鉴定表明，这些调节网络的破坏可能导致 BP 的复杂表型。