Neurotrophin and Synaptic Plasticity

神经营养蛋白和突触可塑性

• 批准号: 6912654
• 负责人: MU-MING POO
• 金额: $ 35.79万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-24 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912654
• 关键词: Xenopus; biological signal transduction; brain derived neurotrophic factor; developmental neurobiology; gene targeting; genetically modified animals; hippocampus; intracellular transport; laboratory mouse; laboratory rat; mesencephalon; morphology; neural plasticity; neural transmission; neuronal transport; neurons; neuropharmacology; protein biosynthesis; protein transport; retina; synapses; synaptogenesis; tissue /cell culture; transfection; voltage /patch clamp

DESCRIPTION (provided by applicant): Neurotrophins (NTs), a family of proteins essential for the survival and differentiation of developing neurons, have been shown to participate in activity-dependent synaptic plasticity. In this project, we propose to test the hypothesis that secretion of NTs at developing synapses is triggered by synaptic activity in a spike pattern-dependent manner and localized synaptic actions of secreted NTs in turn produce long-term functional and structural modification of developing synaptic connections. We will focus our attention on brain-derived neurotrophic factor (BDNF), a NT widely expressed in the developing nervous system, using a combination of physiological, molecular biological, and optical imaging methods. The proposed research consists of three parts. In PART I, we will use cultures of rat or mouse hippocampal neurons to examine the acute pre- and postsynaptic effects of exogenously-applied BDNF on the function and plasticity of glutamatergic and GABAergic synapses and on axon/dendrite morphology and synaptogenesis. The synapse-specific local actions of BDNF and underlying signaling mechanisms will also be investigated. In PART II, we will study the role of endogenously-secreted BDNF in activity-induced modifications of synaptic function and morphology in hippocampal cultures, activity-dependent BDNF secretion, and intra- and interneuronal trafficking of BDNF. In PART Ill, using developing Xenopus tadpoles, we will examine the in vivo effect of BDNF on the function and plasticity of retinotectal synapses, axon/dendrite dynamics and synaptogenesis in the tectum, and the trafficking and secretion of endogenous BDNF. Finally, we will investigate the role of BDNF in the development of retinotopic map and direction-selective receptive field of tectal neurons. Taken together, these in vitro and in vivo studies provide unique opportunities to address several fundamental cell biological issues concerning the modulatory function of neurotrophins in activity-dependent refinement of developing neural connections, and are likely to yield new information relevant to our basic understanding of physiology and pathology of the developing nervous system.

描述（由申请人提供）：神经营养因子（NTs）是发育中的神经元存活和分化所必需的蛋白质家族，已被证明参与活动依赖性突触可塑性。在这个项目中，我们提出验证一个假设，即在发育中的突触中，NTs的分泌是由突触活动以一种依赖于spike模式的方式触发的，而分泌的NTs的局部突触作用反过来会对发育中的突触连接产生长期的功能和结构改变。脑源性神经营养因子（BDNF）是一种在发育中的神经系统中广泛表达的NT，我们将利用生理学、分子生物学和光学成像方法的结合来关注BDNF。本研究由三个部分组成。在第一部分中，我们将使用大鼠或小鼠海马神经元的培养来检查外源性BDNF对谷氨酸能和gaba能突触的功能和可塑性以及轴突/树突形态和突触发生的急性突触前和突触后影响。BDNF的突触特异性局部作用和潜在的信号传导机制也将被研究。在第二部分中，我们将研究内源性分泌的BDNF在海马培养中活动诱导的突触功能和形态改变、活动依赖性BDNF分泌以及BDNF在神经元内和神经元间运输中的作用。在第二部分中，我们将以发育中的爪蟾蝌蚪为实验对象，研究体内BDNF对视网膜顶突触功能和可塑性的影响、顶叶轴突/树突动力学和突触发生的影响，以及内源性BDNF的运输和分泌。最后，我们将探讨BDNF在顶盖神经元视网膜定位图和定向选择感受野发育中的作用。综上所述，这些体外和体内研究提供了独特的机会来解决几个基本的细胞生物学问题，这些问题涉及神经营养因子在发育中的神经连接的活动依赖性改进中的调节功能，并且可能产生与我们对发育中的神经系统的生理学和病理学的基本理解相关的新信息。