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

项目主任/首席调查员(最后、第一、中间)：张美贤 项目摘要/摘要 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。它是 现在普遍认为，在海马齿状回中不断产生新的神经元 成年哺乳动物的大脑，这种神经发生被认为是抑郁症的治疗靶点 治疗。治疗重度抑郁症最常用的处方之一，氟西汀，一种选择性 5-羟色胺再摄取抑制剂，已知可促进成年海马齿状回的神经发生。 然而，成人抗抑郁作用机制的分子和细胞基础 海马区的神经发生尚不完全清楚。最近，Wnt信号已被发现参与调节 成年海马神经发生过程中神经元命运的指定和神经母细胞的增殖。秘而不宣 卷曲受体蛋白(SFRP)3是Wnt信号的分泌型抑制因子，在 成年小鼠齿状回。有趣的是，我们的初步研究表明，sFRP3作为一种 用于通过治疗诸如电惊厥等抗抑郁剂而引起的活性依赖调制的底物 治疗(ECT)和氟西汀在成人脑中。它的下调使我们把重点放在了 抗抑郁作用及sFRP3参与其中。此提案工作的指导阶段将 表征sFRP3和抗抑郁药物的特定细胞和分子机制 用免疫组织化学、双光子共聚焦深度成像、 以sFRP3KO和TOPGAL转基因小鼠为靶标1和2的单细胞遗传学方法。 这项工作的意义将提供对成人发育调节机制的理解 神经发生和抗抑郁作用，这将是治疗策略的关键。在独立的 建议阶段，sFRP3作为成人海马区抗抑郁作用的中介功能 将在具体目标3和4中通过电生理方法和行为分析进行识别。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。虽然啮齿动物模型已被证明是了解基因的伟大工具 在功能和疾病方面，也有报道说在啮齿动物模型和 在人类身上。具体地说，我们将定义sFRP3的功能作用和基于成人的抗抑郁剂 非人灵长类猕猴特定目的的神经发生5.所提出的工作是关键的 基于Wnt/β-catenin信号转导的抗抑郁剂在成人中的重要性 海马神经发生。这些发现将为这一关键角色提供强有力的证据 成人神经发生在抗抑郁作用中的作用，这将为进一步的临床研究和 开发新的治疗干预措施。 小灵通398(11/07版)第1页续格式页

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