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Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder

Mie Kubota1, Takaoki Kasahara, Kazuya Iwamoto

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

The International Journal of Neuropsychopharmacology
|April 16, 2010
PubMed

Insights

Mitochondrial DNA polymerase mutant mice show bipolar disorder-like behaviors. Targeting cyclophilin D (CypD) with an inhibitor improved these behaviors, suggesting CypD as a potential therapeutic target for bipolar disorder.

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Mutant mitochondrial DNA polymerase (Polg1) in neurons causes bipolar disorder (BD)-like phenotypes in mice.
  • Gene expression profiles in BD patients and mouse models require further investigation to identify shared biological pathways.

Purpose of the Study:

  • To identify biological pathways associated with bipolar disorder by comparing gene expression data from BD patients and a mouse model.
  • To investigate the role of specific genes, such as PPIF encoding cyclophilin D (CypD), in BD pathogenesis.

Main Methods:

  • Re-evaluation of DNA microarray datasets from post-mortem brains of BD patients and control subjects.
  • Comparison of gene expression profiles between neuron-specific mutant Polg1 transgenic (Tg) mice and wild-type mice.
  • Gene ontology analysis to identify overlapping altered gene expression categories.

Main Results:

  • Sixteen overlapping gene ontology categories were identified between BD patients and the mouse model.
  • PPIF, encoding cyclophilin D (CypD), was consistently down-regulated in both BD patients and Tg mice.
  • A blood-brain barrier-permeable CypD inhibitor ameliorated abnormal behaviors in Tg mice.

Conclusions:

  • Cyclophilin D (CypD) is implicated in the pathophysiology of bipolar disorder.
  • CypD represents a promising therapeutic target for novel bipolar disorder drug development.

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