Vanderbilt Addiction Center

Neocortical Transcriptome Changes in Schizophrenia

Schizophrenia is a complex disorder that is characterized by multiple functional and anatomical changes across the neocortex. Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been associated with deficits of working memory, while functional changes in the superior temporal gyrus (STG) have been related to psychosis. In addition, a functional disconnection between the PFC and STG may contribute to the cognitive symptoms of schizophrenia. Although changes in the expression of individual genes have been reported in both STG and PFC, the transcriptome differences across these regions and the relationship between them remain mostly unknown. The presentation of schizophrenia across genders has been associated with differences in age of onset, symptomathology, premorbid history, neuroimaging findings, drug responsiveness and brain structure. Functional and structural studies suggest that gender differences are present in the STG and PFC of subjects with schizophrenia. However, we do not know if these gender differences reflect (or are reflected by) differences in the underlying transcriptomes. This application is focused around two critical questions: 1) Is there a schizophrenia-related expression profile within and across different brain regions and 2) Are schizophrenia-related expression changes different across genders? In this context, we propose to test seven specific hypotheses using 3 specific aims: Aim 1. Compare gene expression pattern in 12 MALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices. Aim 2. Compare gene expression pattern in 12 FEMALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices. Aims 1 and 2 will share the same methodology, and compare the transcriptomes: A) Using whole genome HG_U133A and B Affymetrix microarrays. B) Using custom-made, high-sensitivity polymer cDNA microarrays. These cDNA polymer arrays, involving our proprietary probes (patent application in progress) will allow us an improved and targeted assessment of many transcripts that are too sparse to be detected by the currently available microarrays. Aim 3. Verify and localize the microarray-uncovered gene expression changes to cell types A) at transcript level using in situ hybridization and B) at protein level using immunohistochemistry.

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