Insights into myelin dysfunction in schizophrenia and bipolar disorder

Abstract

Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.

Integrative genome-wide gene expression and DNA methylation analysis in brain tissue from medication-free suicide decedents and their controls

“…Previous studies have shown that OLs and their precursors are vulnerable to inflammation, oxidative stress and elevated glutamate levels [69], which explains why these cells are affected in multiple neuropathological entities, including Alzheimer's disease, spinal cord injury, Parkinson's disease, and ischemia, as well as during hypoxia [70,71]. OL deficits have also been previously reported in schizophrenia and bipolar disorder [72,73] and direct evidence of altered oxidative stress markers has been detected in OLs from MDD suicide postmortem brain tissues [74]. The coincidence of gene expression patterns between upregulation of immune response and down regulation of maturation of OLs in suicide decedents in our study might suggest a causal relationship between the two.…”

Consolidation of metabolomic, proteomic, and GWAS data in connective model of schizophrenia

“…Ultimately, dysregulation of energy metabolism and lipids metabolism entails to overproduction of reactive oxygen species and immune response. Dysregulation of redox-responsible proteins, including PRDX6, GFAP, MDH and ATPase subunits, have been repeatedly identified in plasma and prefrontal cortex of patients with schizophrenia [41][42][43] . Unfortunately, researchers pay little attention to mechanisms instructing the pathogenesis of schizophrenia.…”

Cracking the Code of Neuronal Cell Fate

“…Despite the role elicited by Olig2 in the adult cerebral cortex under pathological conditions is not yet known, its reduced expression seems to switch cell fate from differentiation to death, contributing to the development of psychiatric disorders and acute/chronic neurodegenerative diseases, including Alzheimer’s disease and Amyotrophic Lateral Sclerosis, while its increased expression has been associated with different brain tumors, supporting its potential utility as therapeutic target for the treatment of both cancer and neurodegeneration [ 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 ]. Of note, several evidence showed that Olig2 deficiency as well as the presence of rare genetic polymorphisms in this gene (i.e., rs1059004) may represent risk factors for cognitive disorders and schizophrenia, through an effect on neuroanatomical connectivity ( Figure 2 ) [ 159 , 164 , 172 , 173 , 174 , 175 , 176 ].…”