Molelcular determinants of synaptic plasticity

突触可塑性的分子决定因素

• 批准号: 8579650
• 负责人: Laura Bianchi
• 金额: $ 40.81万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579650
• 关键词: Address; Animal Model; Animals; Antibodies; Architecture; Behavior; Biological; Biological Assay; Brain; Caenorhabditis elegans; Cations; Cells; Complex; Development; Dorsal; Event; Excision; Family; Feedback; Figs - dietary; Genes; Goals; Human; Immunoelectron Microscopy; Immunofluorescence Immunologic; Ion Channel; Learning; Link; Location; Mammals; Memory; Methods; Modeling; Molecular; Molecular Genetics; Monovalent Cations; Motor Neurons; Muscle; Nematoda; Nervous system structure; Neurons; Organism; Pathway interactions; Phylogeny; Physiological; Program Development; Proteins; RNA Interference; Regulation; Role; Side; Signal Transduction; Site; Staining method; Stains; Structure; Synapses; Synaptic plasticity; Testing; Transcript; Work; Xenopus oocyte; base; chicken ovalbumin upstream promoter-transcription factor; cholinergic; design; epithelial Na+ channel; extracellular; gamma-Aminobutyric Acid; genetic analysis; human disease; member; mutant; neural circuit; novel; postsynaptic; presynaptic; programs; public health relevance; reconstitution; relating to nervous system; research study; sensor; tool; transcription factor

DESCRIPTION (provided by applicant): Developing neural circuits are actively remodeled as synapses are created in new locations and dismantled in others. These dynamic events are regulated by neuronal activity to produce mature circuits with specific physiological functions. This phenomenon has been observed throughout animal phylogeny which suggests that the underlying pathways are conserved. However, the molecular mechanisms that drive synaptic remodeling are largely unknown. Here we propose a strategy that exploits the simple model organism, C. elegans, to define a development program that remodels the synaptic architecture of a GABAergic circuit. Ventral synapses for DD class GABA neurons are relocated to new sites on the dorsal side during larval development. This synaptic remodeling program is blocked by the UNC-55/COUP-TF transcription factor in VD motor neurons which normally synapse with ventral muscles. We exploited this UNC- 55 function in a powerful cell-specific profiling strategy that identified 19 conserved genes with roles in synaptic remodeling. We have now shown that one of these UNC-55 targets, the DEG/ENaC cation channel, UNC-8, promotes synaptic remodeling in a mechanism that is activated by GABAergic signaling. This finding is important because DEG/ENaC proteins have been implicated in learning and memory but the mechanism that links DEG/ENaC function to synaptic plasticity is poorly understood. Specific Aim 1 tests the key prediction that UNC-8 is closely associated with GABAergic synapses that are remodeled by UNC-8 activity. Specific Aim 2 is designed to test the novel hypothesis that a Ca2+-dependent mechanism links neural activity to UNC-8 cation transport in a feedback loop that dismantles the presynaptic machinery. Specific Aim 3 defines the cellular origin and molecular components of the proposed activity-dependent pathway that regulates UNC-8 and promotes GABAergic synaptic remodeling. Together, these approaches offer a powerful opportunity to delineate an intricate molecular pathway that controls synaptic plasticity. Moreover, the conservation of these remodeling components in mammals argues that the results of this work are likely to reveal fundamental mechanisms that regulate synaptic plasticity in the human brain.

描述（由申请人提供）：由于在新位置创建突触并在其他地方拆除，开发神经回路会积极重塑。这些动态事件受神经元活性调节，以产生具有特定生理功能的成熟电路。在整个动物系统发育中都观察到了这种现象，这表明潜在的途径是保守的。但是，驱动突触重塑的分子机制在很大程度上是未知的。在这里，我们提出了一种利用简单模型有机体C. exemans的策略，以定义一个开发程序，该计划重塑了GABA能电路的突触结构。幼虫发育过程中，DD类GABA神经元的腹侧突触已重新定位到背侧的新位置。该突触重塑程序被VD运动神经元中的UNC-55/Coup-TF转录因子阻止，该神经元通常与腹肌突触。我们在强大的细胞特异性分析策略中利用了这种UNC-55功能，该策略确定了19个具有突触重塑中作用的保守基因。现在，我们已经表明，这些UNC-55目标之一，即DEG/ENAC阳离子通道UNC-8，促进了通过GABAergic信号传导激活的机制中的突触重塑。这一发现很重要，因为DEG/ENAC蛋白已与学习和记忆有关，但是将DEG/ENAC功能与突触可塑性联系起来的机制知之甚少。特定目标1测试了关键预测，即UNC-8与由UNC-8活性重塑的GABA能突触密切相关。特定目标2旨在检验新的假设，即Ca2+依赖性机制将神经活动与拆除突触前机械的反馈回路中的UNC-8阳离子转运联系起来。特定目标3定义了调节UNC-8并促进GABA能突触重塑的拟议活性依赖性途径的细胞起源和分子成分。这些方法共同提供了一个有力的机会来描述控制突触可塑性的复杂分子途径。此外，哺乳动物中这些重塑成分的保存认为，这项工作的结果可能揭示了调节人脑突触可变性的基本机制。