Numerous lines of inquiry implicate connectivity as a central abnormality in schizophrenia. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphologic abnormalities in the oligodendroglia demonstrated in schizophrenic brains are all examined in light of the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome.

The cross-sectional data reported here suggest less widespread changes in white matter at illness onset in schizophrenia which progress in more chronic states. More definitive conclusions will require follow-up imaging of first-episode schizophrenia patients.

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The disconnectivity syndrome hypothesis of schizophrenia suggests that communication between multiple brain circuits and regions may be disrupted. Microarray studies analysed gene expression in 15 different brain regions derived from 13 persons with schizophrenia and controls. The superior temporal gyrus, cingulate gyrus and hippocampus evidence the greatest numbers of abnormally expressed genes. Gene ontology categorization suggested that gene classes associated with oligodendrocytes and myelin function were among the most profoundly affected. qPCR and additional microarray studies have validated these oligodendrocyte-and myelin-associated findings in independent cohorts. At least some of the affected genes are associated with the regulation of axoglial contacts, axon calibre and the integrity of functional elements involved in signal propagation. The confluence of emerging evidence shows that myelination abnormalities are major components of the neurobiology of schizophrenia and suggest that re-evaluation of some long-held hypotheses and beliefs regarding the biological substrates of schizophrenia may be warranted.