Counteracting Effects of Glutathione on the Glutamate-Driven Excitation/Inhibition Imbalance in First-Episode Schizophrenia: A 7T MRS and Dynamic Causal Modeling Study.

Roberto Limongi,Lena Palaniyappan,Peter Jeon,Jean Théberge

doi:10.3390/antiox10010075

Abstract

Oxidative stress plays a key role in the pathophysiology of schizophrenia. While free radicals produced by glutamatergic excess and oxidative metabolism have damaging effects on brain tissue, antioxidants such as glutathione (GSH) counteract these effects. The interaction between glutamate (GLU) and GSH is centered on N-Methyl-D-aspartate (NMDA) receptors. GSH levels increase during glutamate-mediated excitatory neuronal activity, which serves as a checkpoint to protect neurons from oxidative damage and reduce excitatory overdrive. We studied the possible influence of GSH on the glutamate-mediated dysconnectivity in 19 first-episode schizophrenia (FES) patients and 20 healthy control (HC) subjects. Using ultra-high field (7 Tesla) magnetic resonance spectroscopy (MRS) and resting state functional magnetic resonance imaging (fMRI), we measured GSH and GLU levels in the dorsal anterior cingulate cortex (dACC) and blood-oxygenation level-dependent activity in both the dACC and the anterior insula (AI). Using spectral dynamic causal modeling, we found that when compared to HCs, in FES patients inhibitory activity within the dACC decreased with GLU levels whereas inhibitory activity in both the dACC and AI increased with GSH levels. Our model explains how higher levels of GSH can reverse the downstream pathophysiological effects of a hyperglutamatergic state in FES. This provides an initial insight into the possible mechanistic effect of antioxidant system on the excitatory overdrive in the salience network (dACC-AI).

Highlights

The role of oxidative stress in molecular mechanisms of neurodegenerative diseases has been investigated thoroughly [1]; the details of its involvement in pathophysiology of schizophrenia are not completely understood [2]
We studied glutamate levels from the dorsal anterior cingulate cortex and studied the salience network that connects dACC with the anterior insula (AI), using a biologically realistic neural model of resting-state functional magnetic resonance imaging data
We extended this observation to study if GSH influences the glutamate-mediated dysconnectivity in first-episode schizophrenia (FES)

Summary

Introduction

The role of oxidative stress in molecular mechanisms of neurodegenerative diseases has been investigated thoroughly [1]; the details of its involvement in pathophysiology of schizophrenia are not completely understood [2]. While free radicals produced by glutamatergic excess and oxidative metabolism have damaging effects on brain tissue, antioxidants such as glutathione (GSH) counteract the “toxic effect” of oxidative stress [3]. This antioxidant protection is reportedly aberrant in schizophrenia, with some patients having a notable reduction of GSH in the brain [4,5,6] and others with relatively better outcomes having higher than expected levels [7]. GSH levels increase in response to glutamate-mediated excitatory neuronal activity. This increase is Antioxidants 2021, 10, 75.

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