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

T. Kasahara, M. Kubota, T. Miyauchi, Y. Noda, A. Mouri, T. Nabeshima, T. Kato

Research output: Contribution to journalArticle

107 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)577-593
Number of pages17
JournalMolecular Psychiatry
Volume11
Issue number6
DOIs
Publication statusPublished - 01-06-2006

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Mood Disorders
Mitochondrial DNA
Bipolar Disorder
Phenotype
Neurons
Mutation
Chronic Progressive External Ophthalmoplegia
Mitochondrial Diseases
Inborn Genetic Diseases
Estrous Cycle
Sequence Deletion
Tricyclic Antidepressive Agents
Genetic Models
Brain
DNA-Directed DNA Polymerase
Lithium
Transgenic Mice
Antidepressive Agents
Depression
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Kasahara, T. ; Kubota, M. ; Miyauchi, T. ; Noda, Y. ; Mouri, A. ; Nabeshima, T. ; Kato, T. / Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. In: Molecular Psychiatry. 2006 ; Vol. 11, No. 6. pp. 577-593.
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Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. / Kasahara, T.; Kubota, M.; Miyauchi, T.; Noda, Y.; Mouri, A.; Nabeshima, T.; Kato, T.

In: Molecular Psychiatry, Vol. 11, No. 6, 01.06.2006, p. 577-593.

Research output: Contribution to journalArticle

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