Abstract
Impaired glutathione (GSH) synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Our research aimed to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a GSH synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone or in combination, to Sprague–Dawley rats during early postnatal development (p5–p16), on the levels of GSH, sulfur amino acids, global DNA methylation, and schizophrenia-like behavior. GSH, methionine (Met), homocysteine (Hcy), and cysteine (Cys) contents were determined in the liver, kidney, and in the prefrontal cortex (PFC) and hippocampus (HIP) of 16-day-old rats. DNA methylation in the PFC and HIP and schizophrenia-like behavior were assessed in adulthood (p90–p93). BSO caused the tissue-dependent decreases in GSH content and alterations in Met, Hcy, and Cys levels in the peripheral tissues and in the PFC and HIP. The changes in these parameters were accompanied by alterations in the global DNA methylation in the studied brain structures. Parallel to changes in the global DNA methylation, deficits in the social behaviors and cognitive functions were observed in adulthood. Only BSO + GBR 12909-treated rats exhibited behavioral alterations resembling positive symptoms in schizophrenia patients. Our results suggest the usefulness of this neurodevelopmental model for research on the pathomechanism of schizophrenia.
Highlights
Schizophrenia is a chronic, most devastating psychiatric illness affecting about 1% of the world population [1]
In the light of these data, it seems reasonable to suppose that inhibition of GSH synthesis in the rat body during early postnatal life may be a triggering factor for a cascade of events that starting from disturbances in the physiological homeostasis of sulfur amino acids and through further changes in the epigenetic status of some genes in the brain, can lead to the disclosure of schizophrenia-like symptoms in adult rats
GSH levelby and activity in this studypositive indicates that GSH(rplays an between important in level and activity presented in this study indicates that plays an important role in the the maintaining appropriate activity of the hepatic methionine adenosyltransferase (MAT)
Summary
Schizophrenia is a chronic, most devastating psychiatric illness affecting about 1% of the world population [1]. In the light of these data, it seems reasonable to suppose that inhibition of GSH synthesis in the rat body during early postnatal life may be a triggering factor for a cascade of events that starting from disturbances in the physiological homeostasis of sulfur amino acids and through further changes in the epigenetic status of some genes in the brain, can lead to the disclosure of schizophrenia-like symptoms in adult rats To confirm this hypothesis, we performed a comprehensive analysis of the effects of chronic treatment with BSO and GBR 12909, on the content of GSH and sulfur amino acids (Met, Hcy, and Cys) and the global DNA methylation status, as well as on the expression of schizophrenia-like behaviors in Sprague–Dawley rats. We hope that this set of experiments will shed a new light on the mechanisms underlying neurodevelopmental disturbances in schizophrenia
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