Translational Control in Memory and Brain Disorders

项目概要/摘要 在过去 15 年里，包括我的实验室在内的多个实验室已经确定了多种信号通路 在蛋白质合成依赖过程中通过翻译起始因子 eIF4E 和 eIF2α 调节翻译 啮齿动物的持久突触可塑性和各种记忆过程的形式，包括巩固， 听觉和情境威胁记忆的重新巩固和消除。这些发现产生了很多 令人兴奋，因为它们展示了突触可塑性过程中翻译的复杂生化调节 和记忆。尽管取得了这些进展，但有关要求的一些关键和未解决的问题 记忆巩固中的蛋白质从头合成仍然没有答案。我们计划重点关注听觉和 上下文威胁记忆分别确定杏仁核和海马体中的细胞类型 需要 eIF4E 和 eIF2α 依赖的翻译来进行记忆巩固、再巩固、消退和 歧视。我们还计划检查记忆中从头翻译的细胞类型特定要求 使用更复杂类型的行为范式，包括 包括我的实验室在内的许多实验室都表明，翻译失调有助于 阿尔茨海默病 (AD) 等神经退行性疾病中的突触功能障碍和异常行为 以及神经发育障碍，例如脆性 X 综合征 (FXS) 和自闭症谱系障碍 (ASD)。 然而，使用分子方法来剖析这些疾病/病症中的回路功能障碍已经 缺乏。因此，我们计划在小鼠模型中研究细胞类型特异性翻译失调的作用 AD、FXS 和 ASD。此外，我们将识别翻译不当的 mRNA 及其新的 使用我们开发的翻译蛋白和从头蛋白质组学方法合成的蛋白质产品 AD 和 FXS 小鼠模型中翻译/合成不当的 mRNA/蛋白质。 这些问题将通过利用新的突破性的强大的多学科组合来解决 基因工程小鼠和病毒、电生理记录、免疫细胞化学、创新 体内蛋白质从头合成、细胞类型特异性翻译分析和从头测量的方法 蛋白质组学。这些研究的结果将为了解这两个领域的分子事件提供基本见解。 支持记忆巩固、再巩固和消退的兴奋性和抑制性神经元。 此外，这些研究有可能为多种脑部疾病提供治疗靶点，这些疾病 与翻译失调有关。

Project Summary/Abstract Over the last 15 years, several laboratories, including my laboratory, have identified multiple signaling pathways that regulate translation via the translation initiation factors eIF4E and eIF2α during protein synthesis-dependent forms of long-lasting synaptic plasticity and various memory processes in rodents, including the consolidation, reconsolidation, and extinction of auditory and contextual threat memory. These findings have generated much excitement because they demonstrate the complex biochemical regulation of translation during synaptic plasticity and memory. Despite this progress, a number of critical and unresolved questions regarding the requirement for de novo protein synthesis in memory consolidation remain unanswered. We plan to focus on auditory and contextual threat memory to determine the cell types in the amygdala and hippocampus, respectively, that require eIF4E- and eIF2α-dependent translation for memory consolidation, reconsolidation, extinction, and discrimination. We also plan to examine the cell type-specific requirement for de novo translation in memory using more complex types of behavioral paradigms, including Dysregulated translation has been shown by a number of laboratories, including my laboratory, to contribute to synaptic dysfunction and aberrant behaviors in neurodegenerative diseases such as Alzheimer’s disease (AD) and neurodevelopmental disorders such as fragile X syndrome (FXS) and autism spectrum disorder (ASD). However, using molecular approaches to dissect circuit dysfunction in these diseases/disorders has been lacking. Therefore, we plan to examine the role of cell type-specific translational dysregulation in mouse models of AD, FXS, and ASD. Moreover, we will identify the inappropriately translated mRNAs and their newly synthesized protein products using translatomic and de novo proteomic approaches that we developed to identify mRNAs/proteins that are translated/synthesized improperly in mouse models of AD and FXS. These questions will be addressed by utilizing the powerful multidisciplinary combination of new groundbreaking genetically-engineered mice and viruses, electrophysiological recordings, immuno-cytochemistry, innovative methods to measure de novo protein synthesis in vivo, cell-type specific translational profiling, and de novo proteomics. The results of these studies will provide fundamental insights into the molecular events in both excitatory and inhibitory neurons that support consolidation, reconsolidation, and extinction of memory. Moreover, these studies have the potential to provide therapeutic targets for multiple brain disorders that are associated with dysregulated translation.