Control of Dendritic and Synaptic Development by Extracellular Cues

描述（由申请人提供）：重度抑郁症（MDD）是一种复发性精神疾病，大约每6个美国人中就有1人在一生中至少遭受一次折磨。虽然原因可能是多因素的，但MDD的发作与海马结构缺陷相关，包括树突形态的改变。神经营养因子如刺激树突生长的脑源性神经营养因子（BDNF）的水平在患有MDD的人类和MDD的动物模型中均降低。然而，虽然已知BDNF水平的降低与树突状细胞形态的改变相关，但BDNF刺激树突状细胞生长的潜在信号机制尚不清楚。识别这些通路对于了解树突发育和突触发生如何正常发生以及在MDD发作期间如何改变至关重要。我们的长期目标是确定神经营养因子控制树突发育的细胞内信号，并确定这些信号在正常和抑郁的大脑中是如何调节的。本申请的目的是确定一个关键的神经营养因子BDNF控制树突形态发生、突触发生和突触结构维持的信号通路。我们的中心假设是，BDNF刺激树突发育通过一个协调的反应，包括基因组调控的关键蛋白质编码基因和非编码microRNA，其表达在抑郁症期间改变。我们已经制定了这一假设的基础上，我们已发表和未发表的数据，这表明增加CREB依赖的蛋白质编码基因和非编码microRNA的调节是必不可少的BDNF依赖的树突状细胞的生长和突触。这些事件的组合不仅激活促进树突生长的途径，而且抑制抑制树突生长的途径。我们将测试我们的中心假设与以下具体目标：1。确定CREB调节蛋白编码基因在BDNF刺激的树突生长和突触发生中的需求。2.确定在BDNF依赖的树突生长和突触发生中CREB调节的micro-RNA的需求。确定蛋白质编码基因和micro-RNAs在正常发育和BDNF表达改变期间的作用。我们将使用生物化学，遗传学，细胞生物学，行为和成像方法来解决这些具体目标。这项研究的基本原理是，一旦将BDNF与树突和脊柱重塑联系起来的关键信号分子被发现，它们就可以成为治疗和预防MDD的目标。这些研究具有创新性，因为它们将PI在信号转导方面的专业知识应用于一个关键且尚未研究的问题：确定抑郁症期间发生结构变化的分子机制。我们得到了我们的顾问Jaak Panksepp的帮助，他在研究抑郁症模型方面有着丰富的经验。此外，这些结果预计将对该领域产生广泛的影响，因为树突状分支和棘发生异常是多种形式的精神发育迟滞常见的，包括脆性X染色体、唐氏综合征和Rett综合征。

DESCRIPTION (PROVIDED BY APPLICANT): Major Depressive Disorder (MDD) is a recurrent mental illness that afflicts approximately 1 in 6 Americans at least once during their lifetime. While the causes are likely to be multi-factoral, the onset of MDD correlates with structural defects in the hippocampus, including alterations in dendritic morphology. The levels of neurotrophic factors like Brain Derived Neurotrophic Factor (BDNF), which stimulates dendritic growth, are decreased in both humans suffering from MDD and in animal models of MDD. However, while the decrease in BDNF levels is known to correlate with alterations in dendritic morphology, the underlying signaling mechanisms by which BDNF stimulates dendritic growth are unknown. Identifying these pathways is critical to understand how dendritic development and synaptogenesis occurs normally and how it is altered during bouts of MDD. Our long-range goal is to identify the intracellular signals by which neurotrophic factors control dendritic development and to determine how these signals are regulated in both normal and depressed brains. The objective of this application is to determine the signaling pathways by which one critical neurotrophic factor, BDNF, controls dendritic morphogenesis, synaptogenesis and the maintenance of synaptic structures. Our central hypothesis is that BDNF stimulates dendritic development via a coordinated response comprised of genomic regulation of both critical protein-coding genes and non-coding microRNAs whose expression are altered during depression. We have formulated this hypothesis on the basis of our published and unpublished data, which shows that an increase CREB dependent regulation of both protein coding genes and non-coding microRNAs are essential for BDNF dependent dendritic growth and synaptogenesis. The combination of these events not only activates pathways that promote dendritic growth but also inhibits pathways that suppress dendritic growth. We will test our central hypothesis with the following Specific Aims: 1. Determine the requirement of CREB regulated protein coding genes in BDNF-stimulated dendritic growth and synaptogenesis. 2. Determine the requirement for CREB regulated micro-RNAs in BDNF dependent dendritic growth and synaptogenesis. Determine the role of protein coding genes and micro-RNAs in vivo during normal development and during periods of altered BDNF expression. We will use biochemical, genetic, cell biological, behavioral and imaging approaches to address these specific aims. The rationale that underlies the proposed research is that once the critical signaling molecules linking BDNF to dendritic and spine remodeling become known they can be targeted for the treatment and prevention of MDD. These studies are innovative because they apply the expertise of the PI in signal transduction to a critical and under examined problem: to identify the molecular mechanisms underlying structural changes occurring during depression. We have enlisted the help of our consultant Jaak Panksepp, who has extensive experience in studying models of depression. Additionally, these results are expected to have a broad impact on the field as abnormalities in dendritic arborization and spinogenesis are common to numerous forms of mental retardation including Fragile X, Down's, and Rett syndromes.