Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia

Abstract

Schizophrenia (SZ) is a neurodevelopmental disorder with a broad symptomatology, including cognitive symptoms that are thought to arise from the prefrontal cortex (PFC). The neurobiological aetiology of these symptoms remains elusive, yet both impaired redox control and PFC dysconnectivity have been recently implicated. PFC dysconnectivity has been linked to white matter, oligodendrocyte (OL) and myelin abnormalities in SZ patients. Myelin is produced by mature OLs, and OL precursor cells (OPCs) are exceptionally susceptible to oxidative stress. Here we propose a hypothesis for the aetiology of cognitive symptomatology in SZ: the redox-induced prefrontal OPC-dysfunctioning hypothesis. We pose that the combination of genetic and environmental factors causes oxidative stress marked by a build-up of reactive oxygen species that, during late adolescence, impair OPC signal transduction processes that are necessary for OPC proliferation and differentiation, and involve AMP-activated protein kinase, Akt-mTOR-P70S6K and peroxisome proliferator receptor alpha signalling. OPC dysfunctioning coincides with the relatively late onset of PFC myelination, causing hypomyelination and disruption of connectivity in this brain area. The resulting cognitive deficits arise in parallel with SZ onset. Hence, our hypothesis provides a novel neurobiological framework for the aetiology of SZ cognitive symptoms. Future research addressing our hypothesis could have important implications for the development of new (combined) antioxidant- and promyelination-based strategies to treat the cognitive symptoms in SZ.

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

“…Finally, there are also other concepts and hypotheses of SZ, including the cannabinoid hypothesis of SZ [44]. There are also reports about the role of inflammation [45,46] and oxidative stress [47] in this disease.…”

White matter repair and treatment strategy after intracerebral hemorrhage

“…There are studies that show that the production of ectopic aerobic ATP of myelin sheaths is related to the oxidative damage of the myelin sheaths, while the oxidative stress induced by ICH can be shown as demyelination. Demyelination reduces the use of lactic acid produced by the axonal myelin and leads to axonal damage due to axon‐glial metabolic coupling disorder (Table ) …”

“…Demyelination reduces the use of lactic acid produced by the axonal myelin and leads to axonal damage due to axonglial metabolic coupling disorder (Table 1). 35,36…”

On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis

“…Damage from OS on oligodendrocytes and neurons has been found to be associated with active demyelination and axonal or neuronal damage in MS . Studies have revealed that OS modulates OPC signal processes which are vital for OPC proliferation and differentiation resulting in hypomyelination …”

“…47,48 Damage from OS on oligodendrocytes and neurons has been found to be associated with active demyelination and axonal or neuronal damage in MS. 42 Studies have revealed that OS modulates OPC signal processes which are vital for OPC proliferation and differentiation resulting in hypomyelination. 49,50 Moreover, research indicates that myelin sheath can conduct aerobic metabolism, generating ROS which can result in OS. 41 Isolated myelin has been shown to produce OS biomarkers as well as antioxidant defense biomarkers, suggesting that the axonal degeneration associated with myelin loss in demyelinating diseases is related to OS caused by impaired myelin oxidative phosphorylation.…”