Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia

Abstract

Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5–90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.

Changes in Affective Behavior and Oxidative Stress after Binge Alcohol in Male and Female Rats

“…Maas and colleagues, using apomorphine-susceptible (APO-SUS) rat model to study schizophrenia, reported a central role for GSH antioxidant metabolism. They found that treatment with the GSH precursor N -acetylcysteine (NAC) restored not only GSH metabolism but also improved mPFC hypomyelination and cognitive functioning of APO-SUS rats [ 59 ].…”

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…This large body of evidence has led to the claim that various mechanistic strands underlying schizophrenia converge on the “hub of oxidative stress” indexed by GSH [ 48 , 49 ]. Preclinical models with early GSH deficit (i.e., from postnatal day 0 onwards) display various schizophrenia-like features in adult life, including a sensitivity to dopamine excess [ 50 ], and prefrontal hypomyelination [ 51 ]. Nevertheless, chronic peri-adolescent treatment with the glutathione precursor N-acetylcysteine (postnatal days 5–90) restores antioxidant-related and myelin-related mRNA expression improving cognitive flexibility in later life [ 51 ].…”

“…Preclinical models with early GSH deficit (i.e., from postnatal day 0 onwards) display various schizophrenia-like features in adult life, including a sensitivity to dopamine excess [ 50 ], and prefrontal hypomyelination [ 51 ]. Nevertheless, chronic peri-adolescent treatment with the glutathione precursor N-acetylcysteine (postnatal days 5–90) restores antioxidant-related and myelin-related mRNA expression improving cognitive flexibility in later life [ 51 ]. Thus, despite the likely developmental origins of the GSH-deficit, a phenotype ‘rescue’ is possible in preclinical models with interventions in later life.…”

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…Preclinical models with early GSH deficit (i.e. from postnatal day 0 onwards) display various schizophrenia-like features in adult life, including a sensitivity to dopamine excess [50], and prefrontal hypomyelination [51]. Nevertheless, chronic peri-adolescent treatment with the glutathione precursor N-acetylcysteine (postnatal days 5-90) restores antioxidant-related and myelin-related mRNA expression improving cognitive flexibility in later life [51].…”

“…from postnatal day 0 onwards) display various schizophrenia-like features in adult life, including a sensitivity to dopamine excess [50], and prefrontal hypomyelination [51]. Nevertheless, chronic peri-adolescent treatment with the glutathione precursor N-acetylcysteine (postnatal days 5-90) restores antioxidant-related and myelin-related mRNA expression improving cognitive flexibility in later life [51]. Thus, despite the likely developmental origins of the GSH-deficit, a phenotype 'rescue' is possible in preclinical models with interventions in later life.…”