Oxidative Stress and Hypomyelination in the Development of Cognitive Symptoms of Schizophrenia: Studies in the APO-SUS Rat Model
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2015-07-08
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en
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Abstract
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.
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Faculteit der Sociale Wetenschappen