NEUROGENIC TARGETS OF ANTIDEPRESSANT THERAPIES

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DESCRIPTION (provided by applicant): Recent evidence demonstrates a link between the action of antidepressants and increased neurogenesis in the adult hippocampus; moreover, it suggests that neurogenesis may be required for the action of antidepressants. However, it is not known which class of cells within the neuronal differentiation cascade is targeted by the antidepressant drugs and treatments. We have developed a novel approach to identify and classify neuronal precursors and to obtain precise quantitation of changes induced by neurogenic agents. We used this approach to demonstrate that antidepressant fluoxetine affects symmetric division of an early progenitor cell class in the adult hippocampus. In this exploratory application we will use this approach to determine the cellular and gene targets of a range of antidepressant drugs and treatments. In the first series of experiments, we will determine the neurogenic cellular targets of antidepressants of four major families of the drugs (SSRIs, SNRIs, NRIs, and TCAs), of electroconvulsive shock, and of deep brain stimulation. In the second series of experiments we will use laser capture microscopy and transcriptional profiling with microarrays to determine the common gene targets of various antidepressant therapies in neural stem and progenitor cells in the adult hippocampus. Relevance: Emerging evidence implicates adult neurogenesis in the pathophysiology of depression and the action of antidepressants. We here propose to use a novel approach to identify cellular and gene targets for a range of antidepressant drugs and treatments. Our studies will lead to new hypotheses on the mechanisms of action of antidepressants and will help design more specific and effective antidepressant therapies. Emerging evidence implicates adult neurogenesis in the pathophysiology of depression and the action of antidepressants. We here propose to use a novel approach to identify cellular and gene targets for a range of antidepressant drugs and treatments. Our studies will lead to new hypotheses on the mechanisms of action of antidepressants and will help design more specific and effective antidepressant therapies.