Molecular Genetics of Synaptic Plasticity

突触可塑性的分子遗传学

基本信息

批准号：
10368021
负责人：
Laura Bianchi
金额：
$ 43.61万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368021
关键词：
Actins Animal Model Animals Antibodies Architecture Biological Brain Caenorhabditis elegans Calcineurin Calcium Cations Cells Complex Cytoskeleton Development Dorsal Endocytosis Event Excision Feedback Genes Genetic Genetic Programming Genetic Transcription Goals Human Image Learning Link Location Mammals Mediating Membrane Memory Microscopy Modeling Molecular Molecular Genetics Monitor Motor Neurons Muscle Nature Nematoda Nervous system structure Neurons Organism Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Phylogeny Process Program Development Protein Family Protein-Serine-Threonine Kinases Proteins RNA Interference Recycling Regulation Resolution Role Shapes Side Synapses Synaptic plasticity Testing To specify Work chicken ovalbumin upstream promoter-transcription factor epithelial Na+ channel experimental analysis experimental study gamma-Aminobutyric Acid genetic analysis genetic approach genome editing human disease member mutant neural circuit novel polymerization postsynaptic predictive modeling presynaptic programs reconstruction relating to nervous system tool transcription factor transcriptome sequencing

项目摘要

Developing neural circuits are actively remodeled as synapses are created in new locations and dismantled in others. These dynamic changes are driven by the combined effects of genetic programs and neural activity that together shape the architecture and function of mature circuits. Synaptic plasticity has been observed throughout animal phylogeny which suggests that the underlying pathways are conserved and thus can be investigated in simple model organisms that are amenable to experimental analysis. Here we propose to use the nematode, C. elegans, to define a development program that remodels the synaptic architecture of a GABAergic circuit. During early larval development, DD-class GABAergic neurons undergo a dramatic remodeling program in which the presynaptic apparatus exchanges locations with postsynaptic components within the DD neuronal process. To reveal the mechanism of this effect, we are investigating the functional roles of ~20 conserved genes that we have determined are transcriptionally regulated to drive GABA neuron remodeling. Our work has shown that two of these targets, the DEG/ENaC cation channel protein, UNC-8, and ARX-5/p21, a conserved component of the Arp2/3 complex, function together in an activity-dependent mechanism that dismantles the presynaptic domain. Aim 1 tests the hypothesis that UNC-8 cation transport elevates intracellular calcium to drive presynaptic disassembly and that this effect is regulated by calcium- dependent phosphorylation. This goal is important because members of the DEG/ENaC protein family have been implicated in learning and memory but the mechanism that links DEG/ENaC function to synaptic plasticity is poorly understood. Aim 2 tests the hypothesis that the UNC-8 function triggers an actin-dependent endocytic mechanism that recycles presynaptic components for reassembly at new locations. These experiments derive from our surprising discovery that a key functional protein of the Arp2/3 actin-branching complex is transcriptionally regulated to effect synapse removal and that newly identified components of an endocytic recycling pathway are involved. Together, these approaches offer a powerful opportunity to delineate intricate molecular pathways that link neural activity to genetic programming in the execution of a synaptic remodeling mechanism. Moreover, the conservation of C. elegans remodeling components in mammals argues that this work is likely to reveal fundamental mechanisms that regulate synaptic plasticity in the human brain.

由于在新位置创建突触并拆除，开发神经电路会积极重塑其他的。这些动态变化是由遗传程序和神经活动的综合作用驱动的这共同塑造了成熟电路的结构和功能。已经观察到突触可塑性在整个动物系统发育中，表明潜在的途径是保守的，因此可以是在简单的模型生物体中进行了研究，这些生物可以接受实验分析。我们建议在这里使用线虫秀丽隐杆线虫定义了一个开发程序，该程序重塑了 GABA能电路。在早期幼虫发育期间，DD级GABA能神经元发生戏剧性重塑程序，突触前设备与突触后组件交换位置在DD神经元过程中。为了揭示这种效果的机制，我们正在研究功能我们确定的约20个保守基因的作用在转录上调节以驱动GABA神经元重塑。我们的工作表明，其中两个目标是DEG/ENAC阳离子通道蛋白UNC-8和 ARX-5/P21，ARP2/3复合物的保守成分拆除突触前域的机制。 AIM 1检验了UNC-8阳离子运输的假设升高细胞内钙以驱动突触前拆卸，并且这种作用受钙调节依赖性磷酸化。该目标很重要，因为DEG/ENAC蛋白家族的成员具有与学习和记忆有关，但是将DEG/ENAC功能与突触可塑性联系起来的机制理解很差。 AIM 2检验了UNC-8功能触发肌动蛋白依赖性的假设回收新位置重新组装突触前成分的内吞机制。这些实验来自我们令人惊讶的发现，即ARP2/3肌动蛋白分支的关键功能蛋白复合物在转录上调节以实现突触的去除，并新确定的成分涉及内吞回收途径。这些方法共同提供了有力的划定机会在执行突触中，将神经活动与遗传编程联系起来的复杂分子途径重塑机制。此外，在哺乳动物中保存秀丽隐杆线虫的重塑成分认为这项工作可能揭示了调节人类突触可塑性的基本机制脑。