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

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。现在普遍认为，成年哺乳动物海马齿状回中不断产生新的神经元，并且这种神经发生已被认为是抑郁症治疗的治疗靶点。氟西汀是一种选择性5-羟色胺再摄取抑制剂，是治疗重性抑郁症最常用的处方药之一，已知可增强成人海马神经发生。然而，抗抑郁药对成年海马神经发生作用机制的分子和细胞基础尚未完全清楚。最近，Wnt信号转导已被牵连在调节神经元的命运规范和成神经细胞增殖在成年海马神经发生。分泌型卷曲受体蛋白3（Secreted frizzled receptor protein 3，sFRP 3）是Wnt信号通路的抑制剂，在成年小鼠的齿状回高度表达。我们的初步研究表明，sFRP 3作为抗抑郁药后活动依赖性调节的底物。sFRP 3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。该建议的指导阶段旨在表征sFRP 3和抗抑郁药在特定目标1和2中成人海马神经发生中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。在该提案的独立阶段，将使用特定目标3和4中的电生理方法和行为分析来确定sFRP 3作为成年海马中抗抑郁作用的介体的功能作用。这组实验将使我们能够区分sFRP 3在神经发生独立的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然难以捉摸，这项研究具有至关重要的意义。成年海马神经发生中Wnt/α-连环蛋白信号的相互作用。我们的研究结果应该提供一个强有力的证据，成年神经发生在抗抑郁作用中发挥着重要作用，这反过来又将是进一步的临床研究和开发新的治疗干预措施的基础。

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.