Oxidative Stress and Hypomyelination in the Development of Cognitive Symptoms of Schizophrenia: Studies in the APO-SUS Rat Model

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Schizophrenia (SZ) is a devastating neuropsychiatric disorder. The neurobiological aetiology of the cognitive symptoms of this disorder (i.e. poor executive functioning) remains unknown. Cognitive symptoms are thought to arise in the prefrontal cortex (PFC) with PFC hypomyelination, occurring during SZ disease onset, being an important factor involved. The hypomyelination is hypothesized to be caused by an inability of oligodendrocytes to mature and produce myelin due to high levels of oxidative stress that negatively influence signal transduction mechanisms necessary for these processes. Using the apomorphine-susceptible (APO-SUS) rat model for SZ and their control counterparts (APO-UNSUS), we found aberrant expression of redox-related mRNAs throughout the brain of APO-SUS animals, at both postnatal day (PND) 28 and PND90. Interestingly, at PND90, but not at PND28, we observed a significant downregulation of the mRNA expression of eight myelinrelated genes specific for the mPFC. Hence, an oxidative stress deficit is present before the myelin aberrations appear. These myelin aberrations arise during early adolescence, a similar timeframe as SZ disease onset in humans. Additionally, using a texture discrimination paradigm, we found that PFC-dependent intradimensional set-shifting ability in APO-SUS rats was impaired. Accordingly, this study provides evidence supporting the hypothesis that oxidative stress-related hypomyelination in SZ PFC forms the basis for cognitive symptomatology. Our research could be the basis for the development of new treatment strategies for cognitive symptoms, targeting oxidative stress and myelination in SZ.
Faculteit der Sociale Wetenschappen