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

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents, Tricyclic / pharmacology
  • Antidepressive Agents, Tricyclic / therapeutic use
  • Antimanic Agents / pharmacology
  • Antimanic Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology
  • DNA Polymerase gamma
  • DNA, Mitochondrial / analysis
  • DNA, Mitochondrial / genetics*
  • DNA-Directed DNA Polymerase / genetics*
  • DNA-Directed DNA Polymerase / metabolism
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Lithium Carbonate / pharmacology
  • Lithium Carbonate / therapeutic use
  • Male
  • Mice
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Mood Disorders / complications
  • Mood Disorders / drug therapy
  • Mood Disorders / genetics*
  • Mood Disorders / metabolism
  • Motor Activity / genetics
  • Motor Activity / physiology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Ophthalmoplegia, Chronic Progressive External / complications
  • Ophthalmoplegia, Chronic Progressive External / genetics*
  • Phenotype
  • Prosencephalon / cytology
  • Prosencephalon / drug effects
  • Prosencephalon / metabolism


  • Antidepressive Agents, Tricyclic
  • Antimanic Agents
  • DNA, Mitochondrial
  • Lithium Carbonate
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • Polg protein, mouse