RGD Reference Report - Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. - Rat Genome Database

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

Authors: Kasahara, T  Kubota, M  Miyauchi, T  Noda, Y  Mouri, A  Nabeshima, T  Kato, T 
Citation: Kasahara T, etal., Mol Psychiatry. 2006 Jun;11(6):577-93, 523.
RGD ID: 8694301
Pubmed: PMID:16619054   (View Abstract at PubMed)
DOI: DOI:10.1038/sj.mp.4001824   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
POLGHumanmood disorder  ISOPolg (Mus musculus) RGD 
PolgRatmood disorder  ISOPolg (Mus musculus) RGD 
PolgMousemood disorder  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Polg  (DNA polymerase gamma, catalytic subunit)

Genes (Mus musculus)
Polg  (polymerase (DNA directed), gamma)

Genes (Homo sapiens)
POLG  (DNA polymerase gamma, catalytic subunit)


Additional Information