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：靶源性神经营养因子对神经系统的功能至关重要。 存活和分化的发育神经元。 最近的证据 表明神经营养素，一个与神经生长有关的蛋白质家族， 因子，也可能参与突触的活性依赖性修饰， 连接. 采用大鼠海马培养和爪蟾神经肌肉 文化作为模型系统，申请人提出研究空间 以及神经营养分泌的时间特性和在突触处的作用。 在第一部分中，申请人将研究急性突触前和突触后效应 外源性脑源性神经营养因子（BDNF）对基底突触 海马和神经肌肉的性质和活动诱导的可塑性 突触 使用BDNF和BDNF包被珠的局部递送， 申请人将确定BDNF的空间和时间模式， 行动上 申请人还将检查脑电活动是否 通过改变BDNF的结合、转导或 因素的内在化。 潜在的“门控”和“协同” 还将探索cAMP依赖性过程对BDNF作用的影响。 在第二部分，申请人将检查是否分泌BDNF从 过度表达BDNF或内源性分泌TrkB配体的神经元可 调节突触功效，突触活动是否可以触发 BDNF的局部分泌，以及分泌的BDNF的作用是否 仅限于BDNF分泌部位。 贩卖和分泌 BDNF之后还将使用荧光标记的BDNF。 最后在 第三部分，他们将研究BDNF对结构的长期作用 和突触的功能，确定这种长期行为是否可以 保持突触特异性，是否主动转运，Ca2+信号转导，基因 激活和蛋白质合成，以及激活蛋白激酶， 磷酸酶参与长期BDNF效应的转导。 最后，申请人将研究选择性突触 与长期特异性突触修饰相关的“标签”是由于 活动依赖性上调的接受性的突触， 神经营养作用。 总之，这些体外研究提供了 有独特的机会来解决有关人权的几个基本问题， 神经营养在突触可塑性中的作用，并有望为新的 与我们对神经系统的基本理解相关的信息。