Bipolar disorder (BD), characterized by recurrent mood swings between depression and mania, is a highly heritable and devastating mental illness with poorly defined pathophysiology. Recent genome-wide molecular genetic studies have identified several protein-coding genes and microRNAs (miRNAs) significantly associated with BD. Notably, some of the proteins expressed from BD-associated genes function in neuronal synapses, suggesting that abnormalities in synaptic function could be one of the key pathogenic mechanisms of BD. In contrast, however, the role of BD-associated miRNAs in disease pathogenesis remains largely unknown, mainly because of a lack of understanding about their target mRNAs and pathways in neurons. To address this problem, in this study, we focused on a recently identified BD-associated but uncharacterized miRNA, miR-1908-5p. We identified and validated its novel target genes including DLGAP4, GRIN1, STX1A, CLSTN1 and GRM4, which all function in neuronal glutamatergic synapses. Moreover, bioinformatic analyses of human brain expression profiles revealed that the expression levels of miR-1908-5p and its synaptic target genes show an inverse-correlation in many brain regions. In our preliminary experiments, the expression of miR-1908-5p was increased after chronic treatment with valproate but not lithium in control human neural progenitor cells. In contrast, it was decreased by valproate in neural progenitor cells derived from dermal fibroblasts of a BD subject. Together, our results provide new insights into the potential role of miR-1908-5p in the pathogenesis of BD and also propose a hypothesis that neuronal synapses could be a key converging pathway of some BD-associated protein-coding genes and miRNAs.

中文翻译：

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双相情感障碍相关的microRNA，miR-1908-5p，调节神经元谷氨酸能突触中功能基因的表达。

躁郁症（BD）的特征是抑郁症和躁狂症之间反复发作的情绪波动，是一种遗传性和破坏性极强的精神疾病，病理生理学定义不清。最近的全基因组分子遗传学研究已经确定了几种与BD显着相关的蛋白质编码基因和microRNA（miRNA）。值得注意的是，从BD相关基因表达的某些蛋白质在神经元突触中起作用，这表明突触功能异常可能是BD的关键致病机制之一。然而，相比之下，与BD相关的miRNA在疾病发病机理中的作用仍然未知，这主要是由于缺乏对它们的靶标mRNA和神经元通路的了解。为了解决这个问题，在这项研究中，我们集中于最近鉴定出的与BD相关但未表征的miRNA miR-1908-5p。DLGAP4，GRIN1，STX1A，CLSTN1和GRM4，它们都在神经元的谷氨酸能突触中起作用。此外，对人类大脑表达谱的生物信息学分析表明，miR-1908-5p及其突触靶基因的表达水平在许多大脑区域显示出反相关关系。在我们的初步实验中，用丙戊酸（但不是锂）进行慢性处理后，miR-1908-5p的表达在对照人神经祖细胞中增加了。相反，丙戊酸在源自BD受试者的皮肤成纤维细胞的神经祖细胞中被其降低。总之，我们的结果为miR-1908-5p在BD发病机理中的潜在作用提供了新见解，并提出了一个假设，即神经元突触可能是一些与BD相关的蛋白质编码基因和miRNA的关键融合途径。