Kasahara T, Kubota M, Miyauchi T, Noda Y, Mouri A, Nabeshima T, Kato T
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Mol Psychiatry. 2006 Jun;11(6):577-93, 523. doi: 10.1038/sj.mp.4001824.
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.
双相情感障碍或重度抑郁症尚无既定的遗传模型，这阻碍了对这些情绪障碍的研究。尽管情绪障碍是多因素疾病，但它们有时由单个主要基因缺陷的多效性作用之一表现出来。我们聚焦于慢性进行性外眼肌麻痹（CPEO），患有这种疾病的患者有时会合并情绪障碍。慢性进行性外眼肌麻痹是一种线粒体疾病，伴有由核编码基因（如POLG，线粒体DNA聚合酶）突变导致的线粒体DNA（mtDNA）缺失积累。我们培育了转基因小鼠，其中突变型POLG以神经元特异性方式表达。这些小鼠表现出前脑特异性的线粒体DNA缺陷，并且大脑中的单胺能功能发生了改变。突变小鼠表现出特征性的行为表型，昼夜节律紊乱以及与发情周期相关的强烈周期性活动模式。这些类似情绪障碍的异常行为在三环类抗抑郁药治疗后恶化，而在使用情绪稳定剂锂后得到改善。我们还在一些突变动物中观察到了抗抑郁药诱发的躁狂样行为和长期的活动不规则性。我们的数据表明，大脑中线粒体DNA缺陷的积累导致了类似情绪障碍的精神症状，且对双相情感障碍有相似的治疗反应。这些发现与双相情感障碍的线粒体功能障碍假说相符。
