GENOME

GENOME-WIDE EXPRESSION ANALYSIS

REVEALS DYSREGULATION OF MYELINATION-RELATED GENES IN CHRONIC SCHIZOPHRENIA

Kenneth L. Davis, Joseph Buxbaum,

Monte Buchsbaum, Philip D. Harvey, Patrick R. Hof, Joseph I. Friedman, Daniel G.

Stewart, Yaron Hakak, Allen A. Fienberg, Vahram Haroutunian

The Mount Sinai School of Medicine,

Department of Psychiatry, One Gustave L. Levy Place, New York, NY 10029

Neuropathological and brain imaging

studies suggest that schizophrenia may result from neurodevelopmental

defects.  Cytoarchitectural studies indicate cellular abnormalities

suggestive of a disruption in neuronal connectivity in schizophrenia,

particularly n the dorsolateral prefrontal cortex.  Yet, the molecular

substrates associated with schizophrenia, DNA microarray analysis was used to

assay gene expression levels in post-mortem dorsolateral prefrontal cortex of

schizophrenia and control patients.  The most notable change was the

relative underexpression of myelination-related genes suggesting a disruption in

oligodendrocyte function in schizophrenia.

Myelination and those 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 disease, age-related changes in white matter, evidence for

myelin-related gene abnormalities, and consideration of the factors that impact

oligodendroglial function are examined as support for the hypothesis that

oligodendroglia dysfunction with subsequent abnormalities in myelin maintenance

and repair contribute to the schizophrenic syndrome in a subset of schizophrenic

patients.