NEUROTROPHIN AND ACTIVITY DEPENDENT SYNAPTIC PLASTICITY

神经营养因子和活动依赖性突触可塑性

• 批准号: 2682527
• 负责人: MU-MING POO
• 金额: $ 21.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2682527
• 关键词: Xenopus; calcium flux; cyclic AMP; enzyme activity; growth factor receptors; hippocampus; intracellular transport; laboratory rat; neural plasticity; neuropharmacology; neurotrophic factors; phosphoprotein phosphatase; protein kinase; protein transport; receptor binding; synapses; tissue /cell culture

DESCRIPTION: Target-derived neurotrophic factors are essential for the survival and differentiation of developing neurons. Recent evidence indicates that neurotrophins, a family of proteins related to nerve growth factor, may also participate in activity-dependent modification of synaptic connections. Using rat hippocampal cultures and Xenopus nerve-muscle cultures as model systems, the applicants propose to investigate the spatial and temporal properties of neurotrophic secretion and action at the synapse. In part I, the applicants will examine acute pre- and postsynaptic effects of exogenous brain-derived neurotrophic factor (BDNF) on the basal synaptic properties and activity-induced plasticity at hippocampal and neuromuscular synapses. Using local delivery of BDNF and BDNF-coated beads, the applicants will determine the spatial and temporal patterns in the BDNF action. The applicants will also examine whether electrical activity affects the action of BDNF by altering the binding, transduction, or internalization of the factor. The potential "gating" and "synergistic" effect of cAMP-dependent processes on the BDNF action will also be explored. In part II, the applicant will examine whether secretion of BDNF from neurons overexpressing BDNF or endogenous secretion of TrkB ligands can modulate synaptic efficacy, whether synaptic activity can trigger a localized secretion of BDNF, and whether the action of secreted BDNF is restricted to the site of BDNF secretion. The trafficking and secretion of BDNF will also be followed by using fluorescently tagged BDNF. Finally, in part III, they will examine the long-term actions of BDNF on the structure and function of the synapse, determine whether such long-term actions can retain synapse-specificity, whether active transport, Ca2+ signaling, gene activation and protein synthesis, and activation of protein kinases and phosphotases are involved in the transduction of long-term BDNF effects. Finally, the applicants will examine the possibility that selective synaptic "tag" associated with long-term specific synaptic modification is due to an activity-dependent upregulation of the receptiveness of the synapse to the action of neurotrophic. Taken together, these in vitro studies provide unique opportunities to address several fundamental questions concerning the role of neurotrophic in synaptic plasticity, and promise to contribute new information relevant to our basic understanding of the nervous system.

描述：目标衍生的神经营养因素对于 发展神经元的生存和差异。 最近的证据 表明神经营养蛋白是与神经生长有关的蛋白质家族 因素，也可能参与突触的活动依赖性修饰 连接。 使用大鼠海马培养物和爪蟾神经肌肉 培养物作为模型系统，申请人建议研究空间 神经营养性分泌和作用在突触中的时间特性。 在第一部分中，申请人将检查急性突触前和突触后效应 基础突触的外源性脑源性神经营养因子（BDNF） 在海马和神经肌肉的特性和活性诱导的可塑性 突触。 使用BDNF和BDNF涂层珠的本地交付 申请人将确定BDNF中的空间和时间模式 行动。 申请人还将检查电活动是否 通过改变结合，转导或 因子的内在化。 潜在的“门控”和“协同作用” 还将探索依赖CAMP的过程对BDNF动作的影响。 在第二部分中，申请人将检查BDNF的分泌是否是 过表达BDNF的神经元或TRKB配体的内源性分泌可以 调节突触功效，突触活动是否可以触发A BDNF的局部分泌，以及分泌BDNF的作用是否 仅限于BDNF分泌的位置。 贩运和分泌 也将使用荧光标记的BDNF之后进行BDNF。 最后，在 第三部分，他们将检查BDNF对结构的长期行动 和突触的功能，确定这种长期行动是否可以 保留突触特异性，无论是主动传输，Ca2+信号传导，基因 激活和蛋白质合成，以及蛋白激酶的激活和 磷酸酶参与长期BDNF效应的转导。 最后，申请人将检查选择性突触的可能性 与长期特定突触修饰相关的“标签”是由于 依赖于活动的突触接受性上调 神经营养的作用。 综上所述，这些体外研究提供了 独特的机会来解决有关该问题的几个基本问​​题 神经营养在突触可塑性中的作用，并有望做出新的作用 与我们对神经系统的基本理解有关的信息。