Molecular profiles of schizophrenia in the CNS at different stages of illness

Abstract

Results from clinical and imaging studies provide evidence for changes in schizophrenia with disease progression, however, the underlying molecular differences that may occur at different stages of illness have not been investigated. To test the hypothesis that the molecular basis for schizophrenia changes from early to chronic illness, we profiled genome-wide expression patterns in prefrontal cortex of schizophrenic subjects at different stages of illness, along with their age- and sex-matched controls. Results show that gene expression profiles change dramatically depending on the stage of illness, whereby the greatest number and magnitude of gene expression differences were detected in subjects with short-term illness (≤ 4 years from diagnosis). Comprehensive pathways analyses revealed that each defined stage of illness was associated with dysfunction in both distinct, as well as overlapping systems. Short-term illness was particularly associated with disruptions in gene transcription, metal ion binding, RNA processing and vesicle-mediated transport. In contrast, long-term illness was associated with inflammation, stimulus-response and immune functions. We validated expression differences of 12 transcripts associated with these various functions by real-time PCR analysis. While only four genes, SAMSN1, CDC42BPB, DSC2 and PTPRE, were consistently expressed across all groups, there was dysfunction in overlapping systems among all stages, including cellular signal transduction, lipid metabolism and protein localization. Our results demonstrate that the molecular basis for schizophrenia changes from early to chronic stages, providing evidence for a changing nature of schizophrenia with disease progression.