Translational Control in Memory and Brain Disorders

项目摘要/摘要 在过去的15年里，包括我的实验室在内的几个实验室已经确定了多种信号通路 在依赖蛋白质合成的过程中，通过翻译起始因子eif4E和eif2α来调节翻译 啮齿动物长时间突触可塑性的形式和各种记忆过程，包括巩固， 听觉和语境威胁记忆的重新巩固和消亡。这些发现产生了许多 兴奋是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。尽管取得了这一进展，但关于以下要求的一些关键和悬而未决的问题 记忆巩固中的从头蛋白质合成仍然没有答案。我们计划将重点放在听觉和 上下文威胁记忆分别确定杏仁核和海马体中的细胞类型 需要依赖于eif4E和eif2α的转换来进行内存整合、重新整合、消失和 歧视。我们还计划检查内存中从头翻译的特定细胞类型要求 使用更复杂类型的行为范例，包括 包括我的实验室在内的一些实验室已经证明，失调的翻译对 阿尔茨海默病等神经退行性疾病的突触功能障碍和异常行为 以及神经发育障碍，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/紊乱中的电路功能障碍一直是 缺乏。因此，我们计划研究特定细胞类型的翻译失调在小鼠模型中的作用。 AD、FXS和ASD。此外，我们将识别不适当翻译的mRNAs及其新的 使用我们开发的用于鉴定的翻译蛋白质组和从头蛋白质组方法合成蛋白质产品 在AD和FXS小鼠模型中，翻译/合成不正确的mRNAs/蛋白质。 这些问题将通过利用新的开创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 方法测量体内从头蛋白合成、细胞类型特异性翻译图谱和从头蛋白合成 蛋白质组学。这些研究的结果将提供对这两种情况下分子事件的基本见解 兴奋性和抑制性神经元，支持记忆的巩固、再巩固和消失。 此外，这些研究有可能为多种脑部疾病提供治疗靶点。 与失调的翻译有关。

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.