Molecular Genetics of Synaptic Plasticity

发育中的神经回路被积极地重塑，因为突触在新的位置被创建，并在新的位置被拆除。 他人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 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 这表明，潜在的途径是保守的，因此可以 在简单的模式生物中进行研究，这些模式生物适合于实验分析。在这里，我们建议使用 线虫C. elegans，以定义一个开发程序，重塑突触结构的一个 GABA能回路在早期幼虫发育过程中，DD类GABA能神经元经历了一个戏剧性的变化。 突触前器官与突触后成分交换位置的一种重塑程序 在DD神经元过程中。为了揭示这种效应的机制，我们正在研究功能性 我们已经确定的20个保守基因的作用是转录调节驱动GABA神经元 重塑我们的工作表明，其中两个靶点，DEG/ENaC阳离子通道蛋白，ENA-8， ARX-5/p21是Arp 2/3复合物的保守组分，在活性依赖性的细胞内共同发挥作用。 抑制突触前区的机制。目的1检验了α-8阳离子转运的假设， 升高细胞内钙离子以驱动突触前解体，这种作用受钙离子调节， 依赖性磷酸化这一目标很重要，因为DEG/ENaC蛋白家族的成员具有 但DEG/ENaC功能与突触可塑性的联系机制 是很难理解的。目的2检验以下假设，即α-8功能触发肌动蛋白依赖性 使突触前成分在新的位置重新组装的内吞机制。这些 实验源于我们令人惊讶的发现，Arp 2/3肌动蛋白分支的关键功能蛋白 复合物是转录调节，以实现突触消除和新鉴定的成分， 内吞再循环途径。总之，这些方法提供了一个强大的机会， 在执行突触时，将神经活动与遗传编程联系起来的复杂分子通路 重塑机制此外，C.哺乳动物中的elegans重塑成分 认为这项工作可能揭示调节人类突触可塑性的基本机制， 个脑袋

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.