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.

Keywords: anterior cingulate cortex; cingulum bundle; development; myelin; myelin-related genes.

Figure 1

Human DTI along rostrocaudal axial segments of the entire cingulate gyrus, spanning from area 32 (segment 1) to area 23 (segment 8). (A) FA values showing a significant region × diagnosis effect in the cingulate white matter, with patients with recent-onset schizophrenia displaying the highest FA in most segments, followed by control subjects and then patients with chronic schizophrenia (ANCOVA F_14,567 = 2.42, p = 0.003). (B) The same pattern was noted in cingulate grey matter, also with a significant region × diagnosis effect (ANCOVA F_14,567 = 3.01, p < 0.001). Vertical bars indicate 95% confidence intervals and values are computed for the age covariate at its mean. Normal controls (n = 38), recent-onset schizophrenia (n = 6), chronic schizophrenia (n = 41); sz, schizophrenia; FA, fractional anisotropy.

Figure 2

The cingulate cortex and cingulum bundle. (A) Medial surface view of the human brain, depicting the cingulate gyrus (CG) and the cingulate sulcus (CS). (B) Human flat map of the cingulate cortex and surrounding areas. Note that the anterior cingulate is composed of the subgenual area 25, the paracingulate area 32, and six cytoarchitecturally different subregions of area 24 (24a,b,c,a′,b′,c′, respectively). (C) Human sagittal myelin stain showing the cingulate cortex and the cingulum bundle (arrows) as a thin fiber tract overlying the corpus callosum. (D) The cingulum bundle in the rhesus monkey, as visualized with DTI. Panels (A,B) modified from Vogt et al. (1995), and panel (D) from Schmahmann et al. (2007), with permissions. Scale bars 1 cm.

Figure 3

Myelination during brain maturation in the human. From Yakovlev and Lecours (1967), with permission.

Figure 4

Grey matter and white matter volumes in healthy subjects assessed with MRI. From Sowell et al. (2003), with permission.

Figure 5

Low magnification photomicrograph of a myelin Black Gold stain of a wild-type mouse. Inset depicts the outlined cingulum bundle for analysis of fiber length density. Scale bar 50 μm.

Figure 6

Dendritic arbors and spines in the control and QKI mouse model. (A,B) Arbor analysis showing total dendritic lengths in apical and basal dendrites, *p < 0.05, Student's t-test. (C,D) Dendritic lengths in apical and basal dendrites, as a function of the radial distance from the cell soma, *p < 0.05, two-way ANOVA with Bonferroni's post hoc test (Höistad et al., 2008). (E–H) Dendritic segments of Lucifer yellow-filled neurons in the medial PFC were scanned at high resolution on a confocal laser scanning microscope. 3-Dimentionally reconstructed dendritic segments, 50–100 μm from the cell soma, show hyperspiny dendrites on both the apical and basal branches in the QKI mouse. Scale bar 5 μm.