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

描述（由申请人提供）：抑郁症是最普遍的精神疾病之一，影响着全球超过1.21亿人。现在人们普遍认为，在成年哺乳动物海马齿状回中不断产生新的神经元，这种神经发生已被认为是抑郁症治疗的一个治疗靶点。氟西汀是一种选择性5 -羟色胺再摄取抑制剂，是治疗重度抑郁症最常用的处方之一，已知可增强成人海马神经发生。然而，抗抑郁药对成人海马神经发生作用的分子和细胞基础机制尚不完全清楚。近年来，在成人海马神经发生过程中，Wnt信号被认为与调节神经元命运规范和神经母细胞增殖有关。分泌卷曲受体蛋白3 （sFRP3）作为Wnt信号的抑制剂，在成年小鼠齿状回中高表达。我们的初步研究表明，sFRP3作为抗抑郁药后活性依赖性调节的底物。sFRP3的下调使我们关注抗抑郁作用的机制以及sFRP是如何参与的。本提案的指导阶段旨在在specific Aims 1和2中描述成人海马神经发生中sFRP3和抗抑郁药的特定细胞和分子机制。这项工作的意义将是增加我们对调节成人神经发生和抗抑郁作用的机制的理解，这对治疗策略的发展至关重要。在本提案的独立阶段，sFRP3作为成人海马体抗抑郁作用的中介的功能作用将在Specific Aims 3和4中使用电生理方法和行为分析来确定。这组实验将使我们能够区分sFRP3在神经发生非依赖性突触可塑性和行为反应中的作用。由于抗抑郁药的机制仍然难以捉摸，因此提出的工作至关重要。与Wnt/a-连环蛋白信号在成人海马神经发生中的相互作用。我们的研究结果将为成人神经发生在抗抑郁作用中的重要作用提供强有力的证据，这将为进一步的临床研究和开发新的治疗干预措施奠定基础。

DESCRIPTION (provided by applicant): 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 adult mammalian hippocampus, 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 hippocampal neurogenesis. 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 3 (sFRP3) serves as an inhibitor of Wnt signaling, and is highly expressed in the dentate gyrus of adult mouse. Our preliminary studies have suggested that sFRP3 serves as a substrate for activity-dependent modulation after antidepressant. Down-regulation of sFRP3 led us to focus on the mechanisms of antidepressant actions and how sFRP is involved. The mentored phase of this proposal is designed to characterize specific cellular and molecular mechanisms of sFRP3 and antidepressants in neurogenesis in the adult hippocampus in Specific Aims 1 and 2. The significance of this work will be to increase our understanding of the mechanisms that regulate development of adult neurogenesis and antidepressant action, which is critical for the development of therapeutic strategies. In the independent phase of this proposal, the functional role of sFRP3 as a mediator of antidepressant action in adult hippocampus will be identified using an electrophysiological approach and behavioral analyses 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 responses. The proposed work is of critical importance due to the still elusive mechanism of antidepressants? interaction with Wnt/a-catenin signaling in adult hippocampal neurogenesis. Our results should provide a strong body of evidence concerning the essential role that adult neurogenesis plays in antidepressant action, which will in turn be a foundation for further clinical studies and developing new therapeutic interventions.