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

描述(申请人提供)：抑郁症是最常见的精神疾病之一，全世界有超过1.21亿人受到影响。现在普遍认为，成年哺乳动物海马齿状回不断地产生新的神经元，这种神经发生已被认为是治疗抑郁症的靶点。氟西汀是治疗重度抑郁症最常用的处方药之一，它是一种选择性的5-羟色胺再摄取抑制剂，已知可促进成人海马区的神经发生。然而，抗抑郁作用于成年海马神经发生的分子和细胞基础还不完全清楚。近年来，Wnt信号在成年海马神经发生过程中参与调节神经元命运和神经母细胞的增殖。分泌型卷曲受体蛋白3(SFRP3)是Wnt信号通路的抑制因子，在成年小鼠齿状回中高表达。我们的初步研究表明，sFRP3是抗抑郁药后活性依赖调节的底物。SFRP3的下调使我们专注于抗抑郁作用的机制以及SFRP是如何参与的。这项建议的指导阶段旨在表征sFRP3和抗抑郁药物在成年海马神经发生中的特定细胞和分子机制，具体目标1和2。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，这对开发治疗策略至关重要。在这个方案的独立阶段，sFRP3作为成年海马区抗抑郁作用的媒介的功能作用将通过电生理方法和特定目标3和4的行为分析来确定。这套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。由于抗抑郁药的作用机制仍不清楚，这项拟议的工作至关重要？成年海马神经发生中与Wnt/a-catenin信号的相互作用。我们的结果应该为成人神经发生在抗抑郁作用中扮演的重要角色提供强有力的证据，这将反过来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.