Regulation of Memory by the microRNA/RISC Pathway

项目摘要/摘要 神经科学中剩下的谜团之一是记忆是如何储存几天、几周或一段时间的 好几年了。众所周知，稳定记忆的形成需要蛋白质合成，这是一种 脊椎动物和无脊椎动物共有的记忆特征。蛋白质合成定位于突触是 特别有意义，因为它可能赋予选择性突触变化和神经的稳定修改 巡回赛。但蛋白质合成是如何在神经系统中部署并有助于形成 一个特定的记忆是不清楚的。我们已经使用荧光报告结构来可视化突触蛋白 在果蝇体内形成长期记忆的合成。气味与电击的联系是 与表现出突触特异性特征的局部蛋白质合成相关，以及诱导 信使核糖核酸转运到突触区域。这些记忆特征似乎是由RNA控制的-- 诱导沉默复合体(RISC)在蛋白酶体参与RISC调节的途径中。一个RISC 成分Armitage被发现是泛素化的，并以蛋白酶体依赖的方式降解， 显然有助于释放突触蛋白合成，而不是抑制RISC。 这些观察结果提出了一些对理解这些机制很重要的问题 潜在的记忆。我们能否建立一个细粒度的神经图谱，显示蛋白质合成是在哪里发生的 特定的记忆形式？我们能否绘制一张地图，说明哪里需要对蛋白质合成进行调控？ 突触蛋白合成的时间特征是什么？它们与 将突触维持在稳定的新状态？我们才刚刚开始了解这个角色和 突触的RISC通路的生物化学，但作为这些事件的明显调节，我们认为 这一理解将阐明记忆背后的生化和细胞机制。强者 这项研究做出临床贡献的潜力不应被忽视，因为很明显，这些 这种机制在哺乳动物和人类的突触上起作用。这项研究可能会确定新的目标 帮助患有记忆障碍(例如阿尔茨海默病)和突触的患者的治疗努力 活动(例如，癫痫)。

PROJECT SUMMARY/ABSTRACT One of the remaining mysteries of neuroscience is how memories are stored for periods of days, weeks or years. It has been known for some time that the formation of stable memory requires protein synthesis, a feature of memory common to vertebrates and invertebrates. Protein synthesis localized to the synapse is of special interest because it might confer selective synaptic change and the stable modification of a neural circuit. But how protein synthesis is deployed across the nervous system and contributes to the formation of a particular memory is unclear. We have used fluorescent reporter constructs to visualize synaptic protein synthesis in Drosophila that form a long-term memory. The association of an odor with electric shock was correlated with local protein synthesis that displayed features of synaptic specificity, and the induction of mRNA transport to synaptic regions. These features of memory appeared to be controlled by the RNA- Induced Silencing Complex (RISC) in a pathway involving RISC regulation by the Proteasome. A RISC component, Armitage, was found to be ubiquitinated and degraded in a Proteasome-dependent fashion, evidently contributing to the release of synaptic protein synthesis from RISC suppression. These observations raise a number of questions of importance to understanding the mechanisms underlying memory. Can we build a fine-grained neural map of where protein synthesis occurs as a particular memory forms? Can we build a map of where the regulation of protein synthesis is required? What are the temporal characteristics of synaptic protein synthesis and how are they related to the maintenance of a synapse in a stable new state? We have only begun to understand the role and biochemistry of the RISC pathway at the synapse, but as an evident regulator of these events, we believe this understanding will illuminate the biochemical and cellular mechanisms underlying memory. The strong potential of this study to make clinical contributions should not be overlooked, as it is evident that these mechanisms operate at mammalian and human synapses. This study will likely identify new targets for therapeutic efforts to aid patients with disorders of memory (for example, Alzheimer's Disease) and synaptic activity (for example, epilepsy).