ABSTRACT
Schizophrenia is a brain disorder of unknown etiology. Brain imaging studies have revealed evidence for hypoperfusion of the frontal cortex (hypofrontality) and progressive brain volume reduction in schizophrenic patients. Mild cerebral ischemia (oligemia) has been postulated as a cause of the disorder. If the ischemia hypothesis for the adult brain is correct, genes induced by cerebral ischemia should be increased in the frontal cortex of schizophrenic patients during acute psychosis. Here, we show for the first time through a combined analysis of gene expression data from all the studies of the Stanley Brain Collection covering the Brodmann area 46 of the frontal cortex and employing the well-established Affymetrix HGU133a microarray platform that genes upregulated by cerebral ischemia are significantly overexpressed (4.5-fold) in the frontal cortex of acute schizophrenic patients (representation factor (RF) 4.5, p < 0.0002) and to a lesser degree in chronic patients (RF 3.9, p < 0.008) in comparison to normal controls. Neurodevelopmental-, repair-, inflammation- and synapse-related genes showed no significant change. The difference between acute and chronic schizophrenic patients regarding cerebral ischemia-induced genes was highly significant (RF 2.8, p < 0.00007). The results reported here are in line with evidence from biochemical, cellular, electroencephalographic, brain imaging, cerebral near-infrared spectroscopy, vascular, and genetic association studies. In summary, our genomic analysis revealed a clear ischemic signature in the frontal cortex of schizophrenia patients, confirming the prediction of the adult ischemia hypothesis for this disorder. This finding suggests new possibilities for the treatment and prevention of schizophrenia.
