Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder
Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder
复制标题
双相情感障碍患者过度兴奋的神经元对锂的不同反应。
DOI：
10.1038/nature15526
复制
发表时间：
2015-11-05
期刊：
影响因子：
64.8
通讯作者：
Yao, Jun
中科院分区：
文献类型：
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作者：
Mertens, Jerome;Wang, Qiu-Wen;Yao, Jun
躁郁症是一种复杂的神经精神疾病，其特征是躁狂和抑郁症发作。没有治疗，有15％的患者自杀（1）。因此，它已被世界卫生组织评为发病率和生产力失去的最高疾病（2）。先前的神经病理学研究表明，患有躁郁症或动物模型的患者的大脑发生了一系列改变，例如患者前额叶皮层中的神经胶质细胞数量减少（4），蛋白激酶A和C途径的上调活性（5-7）的活性（5-7）以及神经传递的变化（8-11）。但是，这些变化在躁郁症中的作用和因果关系太复杂了，无法准确确定疾病的病理。此外，尽管有些患者出于锂治疗而出于未知原因表现出显着改善，但其他患者对锂治疗却是难治性的。因此，为躁郁症开发准确而强大的生物学模型是一个挑战。引入诱导多能干细胞（IPSC）技术的引入提供了一种新方法。在这里，我们开发了一种用于人双相情感障碍的IPSC模型，并研究了源自双相情感障碍患者的IPSC的海马齿状回神经元的细胞表型。在RNA测序表达分析的指导下，我们通过使用线粒体测定方法检测到来自躁郁症患者的年轻神经元的线粒体异常。此外，使用斑板钳记录和体细胞CA2+成像，我们观察到了多动的动作电位触发。仅在对锂治疗后反应的患者中，锂治疗才通过锂治疗选择性地反转了躁郁症中年轻神经元的这种过度刺激性的表型。因此，过度兴奋性是双相情感障碍的一种早期内表型，我们在该疾病中的IPSC模型可能有助于开发针对其临床治疗的新疗法和药物。
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide(1). Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity(2). Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models', such as reduced glial cell number in the prefrontal cortex of patients(4), upregulated activities of the protein kinase A and C pathways(5-7) and changes in neurotransmission(8-11). However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.