Linking white and grey matter in schizophrenia: Oligodendrocyte and neuron pathology in the prefrontal cortex

Abstract

Neuronal circuitry relies to a large extent on the presence of functional myelin produced in the brain by oligodendrocytes. Schizophrenia has been proposed to arise partly from altered brain connectivity. Brain imaging and neuropathologic studies have revealed changes in white matter and reduction in myelin content in patients with schizophrenia. In particular, alterations in the directionality and alignment of axons have been documented in schizophrenia. Moreover, the expression levels of several myelin-related genes are decreased in postmortem brains obtained from patients with schizophrenia. These findings have led to the formulation of the oligodendrocyte/myelin dysfunction hypothesis of schizophrenia. In this review, we present a brief overview of the neuropathologic findings obtained on white matter and oligodendrocyte status observed in schizophrenia patients, and relate these changes to the processes of brain maturation and myelination. We also review recent data on oligodendrocyte/myelin genes, and present some recent mouse models of myelin deficiencies. The use of transgenic and mutant animal models offers a unique opportunity to analyze oligodendrocyte and neuronal changes that may have a clinical impact. Lastly, we present some recent morphological findings supporting possible causal involvement of white and grey matter abnormalities, in the aim of determining the morphologic characteristics of the circuits whose alteration leads to the cortical dysfunction that possibly underlies the pathogenesis of schizophrenia.

Prolonged myelination in human neocortical evolution

“…For example, schizophrenia is associated with abnormal myelination of the cortical white matter, particularly in the prefrontal cortex (52). Molecular studies also implicate disrupted myelin-related processes throughout the forebrain, such as CNP and MAG gene or protein expression, in the pathogenesis of schizophrenia (14)(15)(16)(17)(18)(19)(20)(21)(22). Accumulating evidence suggests that adolescence and young adulthood constitute a novel period in the evolution of human neurobiological development (1-4, 7, 28, 49, 53).…”

“…Studies of patients with schizophrenia consistently indicate abnormalities in cortical white matter tracts (12)(13)(14) and decreased myelin-related mRNA and protein expression (15)(16)(17)(18), particularly during adolescence (19). For example, expression of 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and myelin-associated glycoprotein (MAG) is dysregulated in patients with schizophrenia (20)(21)(22).…”

Cingulum bundle white matter in MAG-knockout mice

“…Converging evidence suggests that myelin, and specifically oligodendrocytes, is in some way dysfunctional in schizophrenia [40,49,50].…”

“…MAG has been shown to inhibit neurite outgrowth and impair axonal regeneration and may be involved in maintaining healthy axons [39]. These mice may also exhibit some alterations of pyramidal cell dendritic branching patterns [40]. MAGknockout mice may therefore have disruptions in normal myelinated tract development that are reflected in altered anisotropy or fiber length density.…”

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

“…Structural abnormalities of myelin sheath and regressive changes in oligodendrocytes in the prefrontal cortex and hippocampus may be based on neurodevelopmental disturbances or apoptotic cell death [49][50][51] . Interestingly, the heteromodal association cortex has its main myelination period in young adulthood with first symptoms of schizophrenia appearing 52 . On the molecular level, evidence for disordered myelination has been provided by several microarray studies in brain regions of schizophrenia patients [53][54][55][56][57] .…”