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

D A Maas,A Vallès,B Nait-Oumesmar,V D Eijsink,P De Weerd,G J M Martens,J A Van Hulten,R Panic,J R Homberg

doi:10.1038/s41386-021-00964-0

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.

Highlights

Schizophrenia (SZ) is a severe neurodevelopmental disorder that includes cognitive symptoms arising from the prefrontal cortex (PFC)
As decreased levels of glutathione are associated with both whitematter abnormalities and interneuron maturation defects in the PFC of SZ patients, the question remains whether oxidative stress is a key player and possibly a causative factor in the development of medial PFC (mPFC) interneuron hypomyelination in SZ
Ingenuity Pathway Analysis (IPA) revealed that the two top-enriched canonical pathways were ‘glutathionemediated detoxification’ and ‘glutathione redox reactions I’ (p = 9.24E−10 and ratio = 0.258, and p = 1.52E−04 and ratio = 0.25, respectively, in Benjamini–Hochberg corrected T-test; Supplementary Tables 5-7). quantitative real-time PCR (qPCR) analysis confirmed a dysregulation of glutathione-related genes from these two pathways in the mPFC

Summary

Introduction

Schizophrenia (SZ) is a severe neurodevelopmental disorder that includes cognitive symptoms arising from the prefrontal cortex (PFC). In SZ patients, oxidative stress has been reported in the blood and cerebral spinal fluid as well as the medial PFC (mPFC) and is assumed to be caused by decreased glutathione antioxidant levels [2]. Glutathione antioxidant levels are associated with white-matter integrity in the PFC [5]. In SZ, white-matter abnormalities are presumably caused by defective myelination, correlate with cognitive symptoms [6], occur already before SZ onset and aggravate further following transition to psychosis [7]. As decreased levels of glutathione are associated with both whitematter abnormalities and interneuron maturation defects in the PFC of SZ patients, the question remains whether oxidative stress is a key player and possibly a causative factor in the development of mPFC interneuron hypomyelination in SZ

Methods

Results

Conclusion