Profiling Gene Expression in Major Depression

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DESCRIPTION (provided by applicant): Brain imaging studies have reported that there is a reduction in the volume of the hippocampus of patients with major depressive disorder (MDD). In addition, preclinical studies demonstrate that stress decreases neurotrophic factor expression, reduces adult neurogenesis, and causes atrophy of neurons in the hippocampus. In contrast, studies in our laboratory and others have shown that chronic antidepressant treatment (ADT) increases the expression of neurotrophic factors and increases adult neurogenesis in the hippocampus. Taken together, these findings have contributed to a neurotrophic hypothesis of depression. While these preclinical results are interesting, information on their clinical relevance in the pathophysiology and treatment of MDD is lacking. The focus of the current application is to use microarray analysis to identify the molecular determinants that underlie the decrease in hippocampal volume. Toward this goal, we will characterize the gene expression profile of hippocampal subregions of depressed patients using a custom neurotrophic factor gene chip that we have developed. In addition, we will also use a human whole genome commercial microarray to identify other classes of genes altered in MDD. The hippocampus from matched control and MDD subjects that have already been characterized for changes in the number and size of neurons and glia will be used. In addition, the custom and commercial microarrays will be used for analysis of the hippocampus of schizophrenic subjects, which will determine if the gene expression changes observed in depressed subjects are specific to MDD. Altered gene expression will be confirmed by independent approaches, including RT-PCR and in situ hybridization. We hypothesize that the gene expression profiles generated by these studies will lead to a better understanding of the mechanisms that influence neuronal atrophy, dendritic arborization, cell death and cell survival. These studies will provide important information on the gene expression profile in hippocampus of depressed patients and a link between the molecular mechanism of antidepressant action and the etiology and treatment of MDD.