Regulation of Memory by the microRNA/RISC Pathway

描述(申请人提供)：神经科学中剩下的谜团之一是记忆是如何存储几天、几周或几年的。众所周知，稳定记忆的形成需要蛋白质合成，这是脊椎动物和无脊椎动物共同的记忆特征。定位于突触的蛋白质合成特别令人感兴趣，因为它可能带来选择性的突触变化和神经回路的稳定修饰。但蛋白质合成是如何在整个神经系统中部署并有助于形成特定记忆的，目前尚不清楚。我们已经使用荧光报告结构来可视化果蝇形成长期记忆的突触蛋白合成。气味与电击的关系与局部蛋白质合成有关，这种蛋白质合成具有突触特异性，并诱导mRNA运输到突触区域。这些记忆特征似乎是由RNA诱导沉默复合体(RISC)控制的，在一条涉及蛋白酶体调节RISC的途径中。RISC组分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。这些观察提出了一些重要的问题，以了解记忆的潜在机制。我们能否构建一张精细的神经图谱，显示在特定记忆形成时蛋白质合成发生在哪里？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？它们与保持突触处于稳定的新状态有何关系？我们刚刚开始了解RISC通路在突触中的作用和生物化学，但作为这些事件的明显调节因素，我们相信这种理解将阐明记忆背后的生化和细胞机制。这项研究做出临床贡献的强大潜力不应被忽视，因为很明显，这些机制作用于哺乳动物和人类的突触。这项研究可能会为治疗努力确定新的目标，以帮助患有记忆障碍(例如阿尔茨海默病)和突触活动(例如癫痫)的患者。公共卫生相关性：神经系统的许多病理性和某些发育障碍与记忆的形成、维持或回忆方面的缺陷有关。即使记忆的生化机制不是主要缺陷，增强或恢复记忆的治疗工具也将为患者提供相当大的好处，并减轻此类疾病给社会带来的成本和负担。这项提案中描述的工作直接针对一种新的内存基础机制的表征。对潜在记忆的新生化途径的描述为治疗剂的设计和靶向提供了见解。该项目提供了相当大的潜力，通过最终开发新的治疗剂来造福记忆缺陷患者。

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: Many pathological and some developmental disorders of the nervous system are associated with defects in the formation, maintenance or recall of memories. Even where the biochemical mechanisms underlying memory are not the primary defect, therapeutic tools to enhance or restore memory would offer considerable benefit to the patient and alleviate the cost and burden of such disorders to society. The work described in this proposal is aimed directly at the characterization of a novel mechanism underlying memory. The description of new biochemical pathways underlying memory offers insights into the design and targeting of therapeutic agents. This project offers considerable potential to benefit patients with memory deficiencies via the eventual development of novel therapeutic agents.