Faculty Bibliography

Myelin associated glycoprotein (MAG) is an oligodendrocyte-derived gene whose expression is decreased in schizophrenia. Several measures of white matter integrity appear abnormal in schizophrenia, specifically in the anterior cingulate gyrus. We studied mice lacking MAG as a potential model of dysmyelination. Using the stereological "Space Balls" method, we estimated myelinated fiber length density in the cingulum bundle in adult knockout and control mice. We performed diffusion anisotropy imaging in these animals, measuring fractional anisotropy (FA) in a region of the cingulum bundle. We found no differences in cingulum myelinated fiber length density between the two groups, although we did note an age-related decrease regardless of genotype. No differences were noted in FA either, but an age-related decrease was seen as well. These findings imply that MAG dysfunction alone is not sufficient to cause the white matter alterations seen in schizophrenia.

It has been proposed that schizophrenia results partly from altered brain connectivity. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting reduced volume, altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a 3T Siemens scanner to acquire structural and diffusion tensor imaging in age-and sex-matched groups of 41 adults with chronic schizophrenia, 6 adults with recent-onset schizophrenia, and 38 healthy control subjects. We manually traced the anterior and posterior cingulate gyri on all subjects and then compared the volume and anisotropy across groups for the left and right anterior and posterior cingulate gyri. The anterior cingulate gyrus was divided axially into six equal segments, and the posterior cingulate gyrus into two segments. Volume was calculated for the anterior and posterior gyri, and average anisotropy was then calculated for each individual segment, looking separately at gray and white matter. We found decreased overall relative left and right gray matter volume in the anterior cingulate gyrus in persons with schizophrenia compared with healthy controls. Additionally, in both gray and white matter of the cingulate, we found that recent-onset patients had the highest anisotropy, chronic patients had the lowest, and controls were intermediate. These results provide additional evidence for the presence of both white and gray matter abnormalities in the cingulate gyrus, which has been implicated in schizophrenia.

It has been proposed that schizophrenia results partly from altered brain connectivity. Gene microarray analyses performed in gray matter have indicated that several myelin-related genes normally expressed in oligodendrocytes have decreased expression levels in schizophrenia. These data suggest that oligodendrocytes may be involved in the deficits of schizophrenia and may be decreased in number in the case of disease. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a stereologic nearest-neighbor estimator of spatial distribution to investigate oligodendrocytes in the anterior cingulum bundle using postmortem tissue from 13 chronic schizophrenics and 13 age-matched controls. Using a spatial point pattern analysis, we measured the degree of oligodendrocyte clustering by comparing the probability of finding a nearest-neighbor at a given distance in schizophrenics and controls. At the same time, we also estimated the number and density of oligodendrocytes in the region of interest. In the present study, we found no significant differences in the oligodendrocyte distribution or density in the cingulum bundle between the two groups, in contrast to earlier data from the prefrontal subcortical white matter. These results suggest that a subtler oligodendrocyte or myelin anomaly may underlie the structural deficits observed by brain imaging in the cingulum bundle in schizophrenia.

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.

A recent focus of schizophrenia research is disruption of white-matter integrity as a key facet of this complex disorder. This was spurred, partly, by new imaging modalities, magnetic transfer imaging and diffusion tensor imaging, which showed differences in white-matter integrity and tract coherence in persons with schizophrenia compared to controls. Oligodendrocytes, in particular, have been the subject of increased study after gene microarray analyses revealed that six myelin-related genes specific to oligodendrocytes have decreased expression levels in schizophrenia. Oligodendrocytes have also been shown to be decreased in number in the superior frontal gyrus of subjects with schizophrenia. The MAG knockout mouse, missing a myelin-related gene linked to schizophrenia, may prove to be a useful animal model for the dysmyelination observed in the human disease. Studies currently ongoing on this model have found changes in dendritic branching patterns of pyramidal cells in layer III of the prefrontal cortex. Further characterization of the pathology in these mice is underway.