Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes
Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes
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DOI：
10.1038/sj.mp.4001824
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发表时间：
2006-06-01
影响因子：
11
通讯作者：
Kato, T.
中科院分区：
文献类型：
--
作者：
Kasahara, T.;Kubota, M.;Kato, T.
目前还没有确定的双相情感障碍或严重抑郁的遗传模型，这阻碍了对这些情绪障碍的研究。虽然情绪障碍是一种多因素疾病，但有时会表现为单个主基因缺陷的多因素效应。我们将重点放在慢性进行性眼外肌麻痹(CPEO)上，这些患者有时会有共病的情绪障碍。慢性进行性眼外肌麻痹是一种线粒体疾病，伴有线粒体DNA(MtDNA)缺失的积聚，其原因是Polg(mtDNA聚合酶)等核编码基因的突变。我们产生了转基因小鼠，在其中突变的Polg以神经元特异性的方式表达。这些小鼠表现出前脑特有的线粒体DNA缺陷，并改变了大脑中的单胺类功能。突变小鼠表现出特有的行为表型、扭曲的昼夜节律和与发情周期相关的强健的周期性活动模式。这些类似情绪障碍的异常行为被三环类抗抑郁药物治疗恶化，并被情绪稳定剂锂改善。我们还在一些突变的动物中观察到了抗抑郁剂诱导的躁狂样行为和长期的活动不规律。我们的数据表明，mtDNA缺陷在大脑中的积累会导致类似情绪障碍的精神症状，对双相情感障碍的治疗反应类似。这些发现与双相情感障碍的线粒体功能障碍假说是一致的。
There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.