Molelcular determinants of synaptic plasticity

描述（由申请人提供）：发育中的神经回路被积极重塑，因为突触在新的位置被创建，而在其他位置被拆除。这些动态事件由神经元活动调节，以产生具有特定生理功能的成熟回路。这种现象已经在整个动物胚胎发育过程中观察到，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是未知的。在这里，我们提出了一个策略，利用简单的模式生物，C。elegans，以定义一个开发程序，重塑GABA能电路的突触结构。在幼虫发育过程中，DD类GABA神经元的突触迁移到背侧的新位点。在VD运动神经元中，这种突触重塑程序被正常情况下与腹侧肌肉突触的转录因子β-55/COUP-TF阻断。我们在一个强大的细胞特异性分析策略中利用了这种β- 55功能，该策略确定了19个在突触重塑中起作用的保守基因。我们现在已经表明，这些ENA-55的目标之一，DEG/ENaC阳离子通道，ENA-8，促进突触重塑的机制，是由GABA能信号激活。这一发现很重要，因为DEG/ENaC蛋白与学习和记忆有关，但将DEG/ENaC功能与突触可塑性联系起来的机制知之甚少。特异性目标1测试了以下关键预测：β-8与由β-8活性重塑的GABA能突触密切相关。具体目标2旨在检验新的假设，即钙依赖性机制将神经活动与突触前机制的反馈回路中的β-8阳离子转运联系起来。具体目标3定义了所提出的调节GABA-8和促进GABA能突触重塑的活性依赖性途径的细胞起源和分子组分。总之，这些方法提供了一个强大的机会，描绘一个复杂的分子通路，控制突触可塑性。此外，这些重塑成分在哺乳动物中的保存表明，这项工作的结果很可能揭示调节人类大脑突触可塑性的基本机制。

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.