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

Figure 1

Myelin in the central nervous system. Left, a schematic representation of central nervous system (CNS) cells and their multidirectional interactions. Right, the main protein and lipid components of CNS myelin. Proteomic studies have revealed altered expression of myelin proteins in postmortem brain samples from patients with schizophrenia or bipolar disorder. MBP: Myelin basic protein; CNP: 2’,3’-cyclic nucleotide 3’-phosphodiesterase; PLP: Proteolipid protein; MOG: Myelin-oligodendrocyte glycoprotein; MAG: Myelin-associated glycoprotein.

Figure 2

Main cytoskeletal components of the myelinated axon. Proteomic approaches revealed alterations in most of these components in postmortem brain samples of schizophrenia patients.

Figure 3

White matter alterations in schizophrenia. Solid lines represent the path of the affected white matter tracts, whereas shadowed areas (purple and yellow) show brain regions with diminished white matter density.

Figure 4

White matter alterations in bipolar disorder. Solid lines represent the path of the affected white matter tracts.