Molecular Substrates of Translation in Specific Neuronal Compartments During Memory Storage

 描述（由申请人提供）：尽管我们理解长期记忆（LTM）的巩固需要新的蛋白质合成，但翻译的特定分子底物尚未详细了解。最近的研究已经描述了异常蛋白质合成在几个神经精神疾病。重要的是，已经描述了抑制特定脑区域中的翻译用于治疗创伤后应激障碍（PTSD）的治疗潜力。因此，更好地了解翻译的分子底物将有助于开发新的治疗方法，如创伤后应激障碍。我们自己的研究中提出的这一建议的中心假设是，激活突触前和突触后神经元特定区室中特定mRNA的翻译是建立LTM所必需的。为了验证这一假设，我们将通过探索最近描述的标记多聚核糖体的优点，在突触前和突触后神经元的特定神经元隔室中鉴定翻译的分子底物（陷阱：翻译核糖体亲和纯化）和良好表征的海蜗牛回鳃反射（GWR）的神经回路，具体地，我们将（1）分离和表征从暴露于5HT的GWR的突触前和突触后神经元的体细胞和突触区室免疫沉淀的标记的多核糖体，一种对记忆缺失症的学习很重要的神经递质，（2）通过敲除特定候选物和电生理学分析来表征它们在记忆储存中的功能。我们预计，这些研究将提供有史以来第一次描述的分子基板的翻译在特定的前和突触后的神经回路和他们的时间调节在记忆存储的隔间。此外，这些研究将带来新的见解动态翻译过程中的LTM。这些研究将对我们对神经回路功能和记忆储存的基本理解产生重要的积极影响，并可能导致识别记忆障碍预防和治疗干预的新目标。

 DESCRIPTION (provided by applicant): Despite our understanding that consolidation of long-term memories (LTM) require new protein synthesis, the specific molecular substrates of translation are yet to be understood in detail. Recent studies have described abnormal protein synthesis in several neuropsychiatric disorders. Importantly, therapeutic potential of inhibition o translation in specific brain regions for treating Post-traumatic stress disorder (PTSD) have been described. Thus, better understanding of the molecular substrates of translation will help develop novel therapeutic treatments for disorders such as PTSD. The central hypothesis of this proposal derived from our own studies is that activation of translation of specific mRNAs in specific compartments of pre and postsynaptic neurons is required for establishing LTM. To test this hypothesis, we will identify molecular substrates of translation in specific neuronal compartments of pre and postsynaptic neurons by exploring the advantages of recently described tagging of polyribosomes (TRAP: Translating ribosome affinity purification) and well- characterized neural circuitry of gill-withdrawal reflex (GWR) of marine snail, Aplysia californica Specifically we will (1) isolate and characterize tagged polyribosomes immunoprecipitated from somatic and synaptic compartments of pre and post synaptic neurons of GWR that are exposed 5HT, a neurotransmitter important for learning in Aplysia and (2) characterize their function in memory storage by knockdown of specific candidates and electrophysiological analysis. We anticipate that these studies will provide the first ever description of molecular substrates of translation in specific pre and postsynaptic compartments of a neural circuitry and their temporal regulation during memory storage. Furthermore these studies will bring novel insights into dynamics of translation during LTM. These studies will have an important positive impact on our fundamental understanding of neural circuit function and memory storage and likely lead to identification of new targets for preventive and therapeutic interventions of memory disorders.