图片来源：medicalxpress.com
发表于国际著名杂志Nature上的一项研究结果中，来自索尔克遗传学实验室的科学家通过研究发现，相比正常个体而言，患双相型障碍的患者机体的脑细胞或许对于刺激更加敏感，，双相型障碍患者主要特点为情绪在抑郁和高兴之间会发生严重的波动。文章中研究者首次揭示了在特定的细胞水平下这种双相型障碍影响患者大脑的分子机制，同时研究者还揭示了某些患者为何会对锂疗法产生反应。
双相型障碍影响着超过500万美国人的健康，治疗该疾病一直是科学家面临的巨大挑战，如果患者严重的情绪波动不能通过锂疗法来进行治疗，医生们通常就会联合抗精神病药物进行联合治疗来稳定患者情绪，但通常联合疗法只能帮助患者的某一种情感波动，即双相抑郁的波动或患者情绪疯狂的波动。
为了理解引发双相型障碍的原因，研究者Gage及其同时从6名患者机体中收集了其皮肤细胞来进行研究，将这些皮肤细胞重编程使其成为干细胞，随后研究者诱导这些干细胞来使其发育成为神经元，最后将结果同健康个体进行对比分析；Jerome Mertens说道，正常情况下神经元会被刺激所激活并且产生反应，而我们从6名患者机体收集到的细胞表现地尤为明显，甚至不需要刺激它们就会发现它们的强烈反应。
研究结果发现，其中有3名患者的细胞对锂会产生反应，而在另外3名患者中并没有发现锂可以帮助治疗其情绪波动的表现，下一步研究者检测了患者的细胞是否会对锂产生反应，研究者让其中一部分神经元在包含锂的营养液中生长，随后重新测定这些神经元细胞对锂的敏感性。
尽管来自两组患者机体的神经元在首次测试中的敏感性反应相同，但当暴露于锂中时却反应并不相同，对锂有反应的患者机体的细胞生在在锂溶液中后其兴奋性发生了明显地减弱，没有没有对锂疗法产生反应的患者机体的细胞却依然表现出了高度地活性，相关研究结果并不能帮助解释为何锂对某些患者有效而对其他患者没有反应，但其至少提供了一定的线索来帮助科学家们进行深入地探究。
如今研究者发现神经元在刺激性上也会表现出差异，因此这就可以帮助研究人员来筛选更加有效的治疗双相型障碍的药物，如果一种新型药物可以在细胞水平上帮助逆转这种细胞高度兴奋性，或许就可以帮助治疗双相型障碍。下一步研究人员计划去长期追踪患者机体受影响的细胞来观察是否测定的细胞高度兴奋性可以作为唯一的线索来帮助阐明双相型障碍发生的机制。
doi:10.1038/nature15526
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Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder
Jerome Mertens, Qiu-Wen Wang, Yongsung Kim, Diana X. Yu, Son Pham, Bo Yang, Yi Zheng, Kenneth E. Diffenderfer, Jian Zhang, Sheila Soltani, Tameji Eames, Simon T. Schafer, Leah Boyer, Maria C. Marchetto, John I. Nurnberger, Joseph R. Calabrese, Ketil J. Ødegaard, Michael J. McCarthy, Peter P. Zandi, Martin Alba, Caroline M. Nievergelt, The Pharmacogenomics of Bipolar Disorder Study, Shuangli Mi, Kristen J. Brennand, John R. Kelsoe et al.
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide1. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity2. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models3, such as reduced glial cell number in the prefrontal cortex of patients4, upregulated activities of the protein kinase A and C pathways5, 6, 7 and changes in neurotransmission8, 9, 10, 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 selecively 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.