Molelcular determinants of synaptic plasticity

突触可塑性的分子决定因素

• 批准号: 9037068
• 负责人: Laura Bianchi
• 金额: $ 38.18万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037068
• 关键词: Address; Animal Model; Animals; Antibodies; Architecture; Behavior; Biological; Biological Assay; Brain; Caenorhabditis elegans; Cations; Cells; Complex; Development; Dorsal; Electrophysiology (science); Event; Excision; Family; Feedback; Figs - dietary; Genes; Goals; Health; 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; RNA interference screen; 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; genetic approach; human disease; member; mutant; neural circuit; novel; postsynaptic; presynaptic; programs; 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）：随着突触在新位置产生并在其他位置拆除，发育中的神经回路被积极地重塑。这些动态事件受到神经元活动的调节，产生具有特定生理功能的成熟回路。在整个动物系统发育过程中都观察到了这种现象，这表明潜在的途径是保守的。然而，驱动突触重塑的分子机制在很大程度上尚不清楚。在这里，我们提出了一种策略，利用简单的模型生物体秀丽隐杆线虫来定义重塑 GABA 能回路突触架构的开发程序。在幼虫发育过程中，DD 类 GABA 神经元的腹侧突触被重新定位到背侧的新位置。这种突触重塑程序被 VD 运动神经元中的 UNC-55/COUP-TF 转录因子阻断，这些神经元通常与腹侧肌肉突触。我们在强大的细胞特异性分析策略中利用了 UNC-55 的功能，该策略鉴定了 19 个在突触重塑中发挥作用的保守基因。我们现在已经证明，这些 UNC-55 靶点之一，DEG/ENaC 阳离子通道 UNC-8，通过 GABA 信号传导激活的机制促进突触重塑。这一发现很重要，因为 DEG/ENaC 蛋白与学习和记忆有关，但人们对 DEG/ENaC 功能与突触可塑性之间的联系机制知之甚少。具体目标 1 测试了 UNC-8 与由 UNC-8 活动重塑的 GABA 能突触密切相关的关键预测。具体目标 2 旨在测试新的假设，即 Ca2+ 依赖性机制将神经活动与 UNC-8 阳离子运输在反馈环路中联系起来，从而拆除突触前机制。具体目标 3 定义了所提议的活性依赖性途径的细胞起源和分子成分，该途径调节 UNC-8 并促进 GABA 能突触重塑。这些方法共同提供了一个强大的机会来描绘控制突触可塑性的复杂分子途径。此外，这些重塑成分在哺乳动物中的保守性表明，这项工作的结果可能揭示调节人脑突触可塑性的基本机制。