NEUROTROPHIN AND ACTIVITY DEPENDENT SYNAPTIC PLASTICITY

描述：靶向衍生神经营养因子对 发育中神经元的存活和分化。最近的证据 表明神经营养因子，一种与神经生长相关的蛋白质家族 因子，也可能参与活性依赖的突触修饰 关系。利用大鼠海马区培养物和非洲爪哇神经肌肉 文化作为模型系统，申请者建议调查空间 以及神经营养分泌和突触作用的时间特性。 在第一部分中，申请者将检查突触前和突触后的急性效应。 外源性脑源性神经营养因子对基底突触的影响 海马区和神经肌区的特性和活动诱导的可塑性 突触。使用BDNF和BDNF包被珠的本地递送， 申请者将决定BDNF中的空间和时间模式 行动。申请者还将检查是否有电活动 通过改变BDNF的结合、转导或 要素的内在化。潜在的“门禁”与“协同” CAMP依赖的过程对BDNF作用的影响也将被探索。 在第二部分中，申请人将检查脑源性神经营养因子是否从 过度表达BDNF或TrkB配体内源性分泌的神经元可以 调节突触的效能，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 仅限于脑源性神经营养因子分泌部位。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对结构的长期行动 和突触的功能，决定了这种长期行为是否可以 保留突触特异性，无论是主动转运、钙信号转导还是基因 激活和蛋白质合成，并激活蛋白激酶和 磷酸酶参与了BDNF长期效应的转导。 最后，申请者将研究选择性突触 与长期的特定突触修改相关的“标签”是由于 依赖活动的突触对神经细胞的感受性上调 神经营养作用。总而言之，这些体外研究提供了 独一无二的机会来解决与 神经营养在突触可塑性中的作用，并承诺贡献新的 与我们对神经系统的基本了解相关的信息。

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.