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Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

Molecular Psychiatry volume 11, pages 577–593 (2006)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Mark Mayford (The Scripps Research Institute) for the CaMKIIα promoter constructs (pNN265 and pMM403). We are grateful to staffs in Divisions of Animal Experiments and Common Instrumentations (Research Resources Center, Brain Science Institute [BSI], RIKEN) for technical assistance and members in our laboratory for useful discussions. This work was supported by the Grants for Laboratory for Molecular Dynamics of Mental Disorders, RIKEN BSI, Grant-in-Aid from the Japanese Ministry of Health and Labor, and Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology. T Kasahara is supported by a special postdoctoral researcher fellowship (RIKEN).

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Authors and Affiliations

  1. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan

    T Kasahara, M Kubota, T Miyauchi & T Kato

  2. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya-shi, Aichi, Japan

    Y Noda, A Mouri & T Nabeshima

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  1. T Kasahara
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Correspondence to T Kato.

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Accession Numbers and Electronic-Database Information

The DDBJ/EMBL/GenBank accession numbers of the sequences discussed in this paper are the following: mouse POLG cDNA, AB121698; and C57BL/6J mouse mtDNA AY172335.

The Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/) entry numbers of CPEO are 157640 (caused by mutation in the POLG gene), 609283 (caused by mutation in the ANT1 gene), and 609286 (caused by mutation in the Twinkle gene).

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Kasahara, T., Kubota, M., Miyauchi, T. et al. Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol Psychiatry 11, 577–593 (2006). https://doi.org/10.1038/sj.mp.4001824

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