Dysfunction of cortical circuits may underlie the pathophysiology of schizophrenia. The central theme of the Center focuses on understanding the role of circuitry in dorsolateral prefrontal cortex (DLPFC) in the pathogenesis of schizophrenia. The long term goals of Project 2 are to define the molecular changes in gene expression that are causal to the changes in DLPFC circuit function associated with the disease.
The Specific Aims focus on defining, quantitatively, differences in gene expression patterns in specific cortical areas, including DLPFC areas 9 and 46 and visual cortex area 17 in schizophrenic, non-schizophrenic anti- psychotic treated, and normal subjects. Analysis of multiple candidate genes is now possible using gene approach will be applied to postmortem tissue samples provided by the Human Brain Bank Core and prepared for RNA isolation.
In Specific Aim 2, certain gene families or individual genes that exhibit major increases or decreases in expression, based on chip results, will be analyzed by molecular anatomical methods to reveal changes in distribution in distribution and levels of transcript expression in specific cell populations in DLPFC.
Specific Aim 3, will focus on defining molecular features characteristic of specific components of DLPFC circuitry. Using monkey cortical slices, gene expression patterns unique to pyramidal neurons of layer 3 and layer 5 DLPFC will be investigated by producing single cell cDNA libraries and screening differentially to identify cell type-specific and lamina-specific transcriptions. Novel patterns of expressed genes will be further analyzed by molecular anatomical methods. The three specific aims are designed to test hypothesis that relate patterns of gene expression to the pathophysiology of schizophrenia and to the normal, molecular identify of DLPFC neurons.
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