Jang Yongwoo, Lee Sung Hoon, Lee Byeongjun, Jung Seungmoon, Khalid Arshi, Uchida Kunitoshi, Tominaga Makoto, Jeon Daejong, Oh Uhtaek
Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
J Neurosci. 2015 Aug 26;35(34):11811-23. doi: 10.1523/JNEUROSCI.5251-14.2015.
Bipolar disorder (BD) is a psychiatric disease that causes mood swings between manic and depressed states. Although genetic linkage studies have shown an association between BD and TRPM2, a Ca(2+)-permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of Trpm2 that is frequently found in BD patients, induces loss of function. Trpm2-deficient mice exhibited BD-related behavior such as increased anxiety and decreased social responses, along with disrupted EEG functional connectivity. Moreover, the administration of amphetamine in wild-type mice evoked a notable increase in open-field activity that was reversed by the administration of lithium. However, the anti-manic action of lithium was not observed in the Trpm2(-/-) mice. The brains of Trpm2(-/-) mice showed a marked increase in phosphorylated glycogen synthase kinase-3 (GSK-3), a key element in BD-like behavior and a target of lithium. In contrast, activation of TRPM2 induced the dephosphorylation of GSK-3 via calcineurin, a Ca(2+)-dependent phosphatase. Importantly, the overexpression of the D543E mutant failed to induce the dephosphorylation of GSK-3. Therefore, we conclude that the genetic dysfunction of Trpm2 causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BD. Our findings explain the long-sought etiologic mechanism underlying the genetic link between Trpm2 mutation and BD.
Bipolar disorder (BD) is a mental disorder that causes changes in mood and the etiology is still unknown. TRPM2 is highly associated with BD; however, its involvement in the etiology of BD is still unknown. We show here that TRPM2 plays a central role in causing the pathology of BD. We found that D543E, a mutation of Trpm2 frequently found in BD patients, induces the loss of function. Trpm2-deficient mice exhibited mood disturbances and impairments in social cognition. TRPM2 actively regulates the phosphorylation of GSK-3, which is a main target of lithium, a primary medicine for treating BD. Therefore, abnormal regulation of GSK-3 by hypoactive TRPM2 mutants accounts for the pathology of BD, providing the possible link between BD and TRPM2.
双相情感障碍（BD）是一种导致躁狂和抑郁状态之间情绪波动的精神疾病。尽管基因连锁研究表明BD与TRPM2（一种Ca(2+)通透性阳离子通道）之间存在关联，但这种关联的本质尚不清楚。在此，我们表明D543E（一种在BD患者中经常发现的Trpm2突变）会导致功能丧失。Trpm2基因敲除小鼠表现出与BD相关的行为，如焦虑增加和社交反应减少，同时伴有脑电图功能连接中断。此外，在野生型小鼠中给予苯丙胺会引起旷场活动显著增加，而给予锂可使其逆转。然而，在Trpm2(-/-)小鼠中未观察到锂的抗躁狂作用。Trpm2(-/-)小鼠的大脑显示磷酸化糖原合酶激酶-3（GSK-3）显著增加，GSK-3是BD样行为中的关键元素，也是锂的作用靶点。相反，TRPM2的激活通过钙调神经磷酸酶（一种Ca(2+)依赖性磷酸酶）诱导GSK-3去磷酸化。重要的是，D543E突变体的过表达未能诱导GSK-3去磷酸化。因此，我们得出结论，Trpm2的基因功能障碍导致GSK-3不受控制的磷酸化，这可能导致BD的病理过程。我们的发现解释了长期以来寻求的Trpm2突变与BD之间遗传联系的病因机制。
双相情感障碍（BD）是一种导致情绪变化的精神障碍，其病因仍然未知。TRPM2与BD高度相关；然而，其在BD病因中的作用仍不清楚。我们在此表明TRPM2在导致BD病理过程中起核心作用。我们发现D543E（一种在BD患者中经常发现的Trpm2突变）会导致功能丧失。Trpm2基因敲除小鼠表现出情绪障碍和社交认知受损。TRPM2积极调节GSK-3的磷酸化，GSK-3是治疗BD的主要药物锂的主要靶点。因此，活性不足的TRPM2突变体对GSK-3的异常调节是BD病理的原因，为BD与TRPM2之间提供了可能的联系。
