Molecular Genetics of Synaptic Plasticity

随着突触在新的位置被创建和被拆除，发育中的神经回路被积极地重塑 其他。这些动态变化是由遗传程序和神经活动的综合影响驱动的 这些因素共同塑造了成熟电路的架构和功能。已经观察到突触的可塑性 在整个动物系统发育中，这表明潜在的途径是保守的，因此可以 在易于进行实验分析的简单模型生物中进行研究。在这里，我们建议使用 线虫，线虫，定义一个开发程序，重塑突触结构 GABA能电路。在幼虫早期发育期间，DD类GABA能神经元经历了戏剧性的 突触前装置与突触后部件交换位置的重塑程序 在DD神经元突起内。为了揭示这种效应的机制，我们正在研究功能 我们已确定的转录调控的~20个保守基因在驱动GABA神经元中的作用 改建。我们的工作表明，其中两个靶点，DEG/ENaC阳离子通道蛋白UNC-8和 Arx-5/p21是Arp2/3复合体的一个保守成分，它在一种活性依赖的 拆除突触前区域的机制。目的1检验UNC-8阳离子转运假说 升高细胞内钙以驱动突触前分解，这种作用受钙- 依赖的磷酸化。这一目标很重要，因为DEG/ENaC蛋白家族的成员 与学习和记忆有关，但DEG/ENaC功能与突触可塑性有关的机制 人们对此知之甚少。Aim 2验证了UNC-8功能触发肌动蛋白依赖的假设 回收突触前成分以在新的位置重新组装的内吞机制。这些 实验源于我们惊人的发现，Arp2/3肌动蛋白的一个关键功能蛋白-分支 复合体是转录调控的，以实现突触的移除，而新发现的 参与了细胞内循环途径。总而言之，这些方法提供了一个强大的机会来描绘 在突触的执行中将神经活动与遗传编程联系起来的复杂的分子路径 重塑机制。此外，哺乳动物中线虫重塑成分的保守性 认为这项工作可能揭示调节人类突触可塑性的基本机制 大脑。

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.