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.

Keywords: Myelin sheath; Oligodendroglia; Schizophrenia; Bipolar disorder; White matter

Core Tip: Schizophrenia and bipolar disorder are multifactorial neuropsychiatric entities that share clinical manifestations as well as alterations to brain structure and function, genetic characteristics, and neurobiological pathways. Among the main pathophysiological mechanisms shared by these conditions is oligodendroglial dysfunction. Scientific evidence that ranges from the microscale cellular and subcellular levels to the macroscale connectomic level strongly supports overall myelin dysfunction and brain disconnection as hallmarks of schizophrenia and bipolar disorder.