Lithium-induced gene expression alterations in two peripheral cell models of bipolar disorder

<b>Objectives:</b> The aim of our study was to investigate molecular mechanisms of lithium action by studying the gene expression profile of peripheral cell models generated from bipolar patients (BD) and healthy controls (HC). <b>Methods:</b> EBV-immortalised lymphoblastoid cells (LCLs) and fibroblast cells from BD and HC were incubated with either lithium chloride or plain medium for 3 weeks. We first conducted a microarray gene expression study. The most promising differentially regulated genes in terms of lithium-associated or disorder-associated pathways were then replicated by quantitative real-time PCR (qRT-PCR). <b>Results:</b> The pooled microarray analysis showed 459 genes to be differentially regulated in BD compared to HC and 58 due to lithium treatment in LCLs, and 295 genes to be differentially regulated in BD compared to HC and five due to lithium treatment in fibroblasts. After correction for multiple comparison, <i>EPHB1</i> disorder × treatment interactions remained significant in LCLs validated by qRT-PCR. In the control group, lithium influenced the expression of <i>ANP32E</i>, <i>PLEKHA2</i>, <i>KCNK1</i>, <i>PRKCH</i>, <i>ST3GAL6</i> and <i>AIF1</i>. In bipolar and control fibroblast cells lithium treatment decreased <i>FGF9</i> expression. <b>Conclusions:</b> The differentially regulated genes in our study add evidence for the relevance of inflammation, neuronal/glial development, phosphatidylinositol second-messenger pathway and ion channels in the mode of action of lithium.

<b>研究目标：</b>本研究旨在通过分析双相情感障碍（BD, bipolar disorder）患者与健康对照（HC, healthy controls）来源的外周细胞模型的基因表达谱，探究锂盐作用的分子机制。<b>研究方法：</b>本研究将BD患者与HC来源的爱泼斯坦-巴尔病毒（EBV）永生化淋巴母细胞系（LCLs）及成纤维细胞，分别置于氯化锂培养液或基础培养基中培养3周。首先开展基因芯片基因表达谱分析，随后针对与锂盐作用或疾病相关通路中筛选出的差异表达最显著的基因，采用实时定量聚合酶链式反应（qRT-PCR, quantitative real-time PCR）进行验证。<b>研究结果：</b>合并基因芯片分析结果显示，相较于HC，BD患者样本中存在459个差异表达基因；LCLs中因锂盐处理产生差异表达的基因共58个。而成纤维细胞样本中，相较于HC，BD患者样本存在295个差异表达基因，因锂盐处理产生差异表达的基因共5个。经多重比较校正后，经qRT-PCR验证的LCLs中，<i>EPHB1</i>的疾病×处理交互作用仍具有统计学显著性。在HC组中，锂盐可调控<i>ANP32E</i>、<i>PLEKHA2</i>、<i>KCNK1</i>、<i>PRKCH</i>、<i>ST3GAL6</i>及<i>AIF1</i>的基因表达。在BD患者及HC的成纤维细胞中，锂盐处理均可下调<i>FGF9</i>的基因表达。<b>研究结论：</b>本研究筛选出的差异表达基因，为炎症反应、神经元/神经胶质细胞发育、磷脂酰肌醇第二信使通路及离子通道与锂盐作用机制的相关性提供了新的证据。