Role of sFRP3-Dependent Regulation of Adult Neurogenesis in Antidepressant Action

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Program Director/Principal Investigator (Last, First, Middle): Jang, Mi-Hyeon Project Summary/Abstract Depression is one of the most prevalent mental illnesses, affecting more than 121 million people worldwide. It is now generally accepted that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain, and this neurogenesis has been implicated as a therapeutic target for depression treatment. One of the most commonly prescribed treatments of major depression, fluoxetine, a selective serotonin reuptake inhibitor, is known to enhance adult neurogenesis in the dentate gyrus of the hippocampus. However, the molecular and cellular basis of mechanisms underlying antidepressant action on adult hippocampal neurogenesis is not fully understood. Recently, Wnt signaling has been implicated in regulating neuronal fate specification and neuroblast proliferation during adult hippocampal neurogenesis. Secreted frizzled receptor protein (sFRP) 3 serves as a secreted inhibitor of Wnt signaling, and is highly expressed in the dentate gyrus of adult mouse. Interestingly, our preliminary studies have suggested that sFRP3 serves as a substrate for activity-dependent modulation caused by treatment of antidepressant such as electroconvulsive therapy (ECT) and fluoxetine in adult brain. Its down-regulation led us to focus on the mechanisms of antidepressant actions and involvement of sFRP3 in it. The mentored phase of this proposal work will characterize specific cellular and molecular mechanisms of sFRP3 and antidepressants underlying neurogenesis in the adult hippocampus using the immunohistochemistry, two photon confocal deep imaging, and single cell genetic approach with sFRP3 KO and TOPGAL transgenic mice in Specific Aims 1 and 2. The significance of work will provide understanding of the mechanisms that regulate development of adult neurogenesis and antidepressant action, which will be critical for the therapeutic strategies. In the independent phase of proposals, the functional role of sFRP3 as a mediation of antidepressant action in adult hippocampus will be identified with an electrophysiological approach and behavioral analysis in Specific Aims 3 and 4. This set of experiments will allow us to differentiate roles of sFRP3 in neurogenesis-independent synaptic plasticity and behavioral response. While rodent animal models have been proven to be great tools to understand gene function and diseases, there are also reported differences in the response to drugs in rodent animal models and in humans. Specifically, we will define the functional role of sFRP3 and antidepressant based on adult neurogenesis in nonhuman primate marmoset monkey in Specific Aim 5. The proposed work is of critical importance due to the still elusive mechanism of antidepressant based on Wnt/¿-catenin signaling in adult hippocampal neurogenesis. These discoveries will provide a strong body of evidence to the essential role that adult neurogenesis plays in antidepressant action which will be a foundation for further clinical studies and developing new therapeutic interventions. PHS 398 (Rev. 11/07) Page 1 Continuation Format Page