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

Objectives: 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). Methods: 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). Results: 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, EPHB1 disorder × treatment interactions remained significant in LCLs validated by qRT-PCR. In the control group, lithium influenced the expression of ANP32E, PLEKHA2, KCNK1, PRKCH, ST3GAL6 and AIF1. In bipolar and control fibroblast cells lithium treatment decreased FGF9 expression. Conclusions: 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.研究目的：本研究旨在通过分析双相情感障碍（bipolar disorder, BD）患者与健康对照（healthy controls, HC）来源的外周细胞模型的基因表达谱，探究锂盐发挥作用的分子机制。 研究方法：将EB病毒永生化淋巴母细胞（EBV-immortalised lymphoblastoid cells, LCLs）以及双相情感障碍患者与健康对照来源的成纤维细胞，分别置于氯化锂培养基或普通培养基中培养3周。首先开展基因芯片表达谱分析；随后针对与锂盐作用通路或疾病相关通路中最具潜力的差异调控基因，通过实时定量聚合酶链反应（quantitative real-time PCR, qRT-PCR）进行验证。 研究结果：合并基因芯片分析结果显示，与健康对照相比，双相情感障碍患者的淋巴母细胞中有459个差异调控基因，锂盐处理组与对照组相比有58个差异调控基因；而成纤维细胞中，与健康对照相比有295个差异调控基因，锂盐处理组与对照组相比有5个差异调控基因。在校正多重比较后，经qRT-PCR验证的淋巴母细胞中EPHB1的疾病×处理交互作用仍具有统计学显著性。在健康对照组中，锂盐可影响ANP32E、PLEKHA2、KCNK1、PRKCH、ST3GAL6及AIF1的基因表达。在双相情感障碍患者及健康对照的成纤维细胞中，锂盐处理均可降低FGF9的表达水平。 研究结论：本研究鉴定的差异调控基因，为炎症反应、神经元/神经胶质发育、磷脂酰肌醇第二信使通路及离子通道参与锂盐作用机制提供了新的证据支持。