Molecular Characterization of Schizophrenia Viewed by Microarray Analysis of Gene Expression in Prefrontal Cortex.pdfVIP

Neuron, Vol. 28, 53–67, October, 2000, Copyright ?2000 by Cell Press Molecular Characterization of Clinical Study Schizophrenia Viewed by Microarray Analysis of Gene Expression in Prefrontal Cortex Ka′ roly Mirnics,*?§ Frank A. Middleton,* Adriana Marquez,* David A. Lewis,? and Pat Levitt*? * Department of Neurobiology ? Departments of Psychiatry and Neuroscience ? PittArray University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania 15261 Summary Microarray expression profiling of prefrontal cortex from matched pairs of schizophrenic and control subjects and hierarchical data analysis revealed that transcripts encoding proteins involved in the regulation of presynaptic function (PSYN) were decreased in all subjects with schizophrenia. Genes of the PSYN group showed a different combination of decreased expression across subjects. Over 250 other gene groups did not show altered expression. Selected PSYN microarray observations were verified by in situ hybridization. Two of the most consistently changed transcripts in the PSYN functional gene group, N-ethylmaleimide sensitive factor and synapsin II, were decreased in ten of ten and nine of ten subjects with schizophrenia, respectively. The combined data suggest that subjects with schizophrenia share a common abnormality in presynaptic function. We set forth a predictive, testable model. Introduction Schizophrenia is a complex and devastating brain disorder that affects 1% of the population and ranks as one of the most costly disorders to afflict humans (Carpenter and Buchanan, 1994; Hyman, 2000b). This disorder typically has its clinical onset in late adolescence or early adulthood, presenting as a constellation of both positive (delusions, hallucinations, and thought disorganization) and negative (impaired motivation and decreased emotional expression) symptoms (Lewis, 2000). Alterations in cognitive processes, such as attention and working memory, however, may be present prior to the onset of the clinical s