miRNA regulation of CPEB and its role in synapse-specific facilitation and memory

描述(由申请人提供)：本提案中描述的研究调查了miRNAs及其对突触相关RNA结合蛋白CPEB的调节在维持突触特异性促进和长期记忆中的作用。CPEB因其在增强突触易化方面的作用而被广泛研究，并因其作为突触标签的潜在作用以及其优先性质而引起人们的兴趣，这些性质可以在最初的刺激被去除后多年保持突触的强度。然而，我们缺乏对其调控和导致其持续突触特异性活动的机制的任何了解。MiRNAs是一类新兴的非编码小RNA，是基因表达的重要转录后调控因子。我们有初步数据支持miRNAs是CPEB的关键调节因子的观点。因此，我希望在探索miRNAs对CPEB的突触特异性调控效应时，我们不仅能深入了解神经递质如何局部调节mlNRA，而且重要的是，为突触如何转换到并维持翻译活性状态提供一种机制。我通过以下具体目标来解决这些问题：目标1：哪些miRNAs直接靶向并调控海兔CPEB？目的2：这些miRNAs中哪些受5-羟色胺调节，以及如何调节？目的3：5-羟色胺对CPEB的miRNA调节是否发生在突触局部，是否存在一种反馈机制，可能驱动持续的突触特异性活动？相关性：更深入地了解CPEB，它对突触的调节，以及它对长期记忆的影响，可能会让我们更好地了解遗忘症、成瘾和其他神经疾病，其中神经元连接的灵活性受到损害。

DESCRIPTION (provided by applicant): The research described in this proposal investigates the role of miRNAs and their regulation of a synapse associated RNA binding protein, CPEB, in maintaining synapse-specific facilitation and long term memory. CPEB is well studied for its role in enhancing synaptic facilitation and is interesting for its potential role as a synaptic tag and its priority like properties which could maintain the strength of synapses for years long after the initial stimulus has been removed. However, we lack any understanding of its regulation and the mechanism that give rise to its sustained synapse-specific activity. miRNAs are an emerging class of small non coding RNAs that are important post-transcriptional regulators of gene expression. We have preliminary data to support the idea that miRNAs are key regulators of CPEB. It is my hope, therefore, that in exploring the synapse-specific regulatory effect of miRNAs on CPEB, we gain insight not only into how neurotransmitters locally regulate mlNRAs, but also importantly, provide a mechanism for how synapses transition to, and maintain, translation ally active states. I address these questions using the following specific aims: Aim 1: Which miRNAs directly target and regulate Aplysia CPEB? Aim 2: Which of these miRNAs are regulated by serotonin, and how? Aim 3: Does the serotonin-induced miRNA regulation of CPEB occur locally at synapses and is there a feedback mechanism that might drive persistent synapse-specific activity? Relevance: A deeper understanding of CPEB, its regulation at synapses, and its effect on long term memory will likely give us better insight into amnesias, addiction, and other neurological conditions where the flexibility of neuronal connections is compromised.