Abstract
We developed transgenic (Tg) mice modeling an autosomally inherited mitochondrial disease, chronic progressive external ophthalmoplegia, patients with which sometimes have comorbid mood disorders. The mutant animals exhibited bipolar disorder-like phenotypes, such as a distorted day–night rhythm and a robust activity change with a period of 4–5 days, and the behavioral abnormalities were improved by lithium. In this study, we tested the effect of electroconvulsive stimulation (ECS) on the behavioral abnormalities of the model. Electroconvulsive therapy, which has long been used in clinical practice, provides fast-acting relief to depressive patients and drug-resistant patients. We performed long-term recordings of wheel-running activity of Tg and non-Tg mice. While recording, we administrated a train of ECS to mice, six times over two weeks or three times over a week. The treatment ameliorated the distorted day–night rhythm within three times of ECS, but it had no effect on the activity change with a period of 4–5 days in the female mice. To study the mechanism of the action, we investigated whether ECS could alter the circadian phase but found no influence on the circadian clock system. The potent and fast-acting efficacy of ECS in the mutant mice supports the predictive validity of the mice as a model of bipolar disorder. This model will be useful in developing a safe and effective alternative to lithium or electroconvulsive therapy.
Highlights
Bipolar disorder is a major mental disorder characterized by recurrent manic and depressive episodes
We delivered electroconvulsive stimulation (ECS) six times over 2 weeks in the first experiment (Fig. 1A); this treatment schedule conformed to the standard electroconvulsive therapy (ECT) regime for patients with mood disorder
ECS seemed to improve the distorted day–night rhythm of the mutPOLG Tg mice; more than half of the treated mice died after ECS probably due to respiratory failure, and it became impossible to statistically analyze the effect of ECS
Summary
Bipolar disorder is a major mental disorder characterized by recurrent manic and depressive episodes. Linkage analyses and case-control association studies have been conducted, robustly replicated loci susceptible to bipolar disorder have not been identified [2,3]. In this context, several symptom-based animal models have been reported [4,5,6]. CPEO is a rare disease (MIM 157640) inherited in a Mendelian fashion It is characterized by slowly but progressive ptosis and ophthalmoparesis and is associated with mitochondrial DNA (mtDNA) aberrations such as deletions, duplications, and point mutations. Mitochondrial dysfunction in bipolar disorder has been suggested by magnetic resonance spectroscopy, association studies of polymorphisms of mtDNA and nuclear genes encoding mitochondrial protein, and genome-wide gene expression analyses [8]. The POLG gene is reported to be one of the causative genes for CPEO comorbid with mood disorders [9]
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