title: Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models.
abstract: CONCLUSIONS
  Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology.
  
  
  BACKGROUND
  Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination.
  
  
  RESULTS
  Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication.
  
  
  CONCLUSIONS
  These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds.
authors.affiliation: Department of Psychiatry, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly-Lausanne, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Kulak
authors.forename: Pascal
authors.initials: P
authors.lastname: Steullet
authors.forename: Jan-Harry
authors.initials: JH
authors.lastname: Cabungcal
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Andrés
authors.initials: A
authors.lastname: Ingason
authors.forename: Michel
authors.initials: M
authors.lastname: Cuenod
authors.forename: Kim Quang
authors.initials: KQ
authors.lastname: Do
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000172:deficiency; D006801:Humans; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission
chemical_list: D005721:Glutamate-Cysteine Ligase; D005978:Glutathione