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探讨了mirna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因其在增强突触促进中的作用而得到了很好的研究，其作为突触标签的潜在作用及其在初始刺激被移除多年后仍能保持突触强度的优先性也很有趣。然而，我们对其调控和机制缺乏任何理解，导致其持续的突触特异性活动。mirna是一类新兴的小非编码rna，是基因表达的重要转录后调节因子。我们有初步数据支持mirna是CPEB关键调控因子的观点。因此，我希望通过探索mirna对CPEB的突触特异性调控作用，我们不仅能深入了解神经递质如何局部调控mlNRAs，更重要的是，为突触如何过渡到并维持翻译活性状态提供一种机制。我使用以下具体目标来解决这些问题：目标1：哪些mirna直接靶向和调节应用程序CPEB？目标2：哪些mirna受血清素调节，以及如何调节？目的3：血清素诱导的CPEB的miRNA调节是否局部发生在突触上，是否存在一种可能驱动持续突触特异性活动的反馈机制？相关性：对CPEB、其对突触的调控及其对长期记忆的影响的更深入了解，可能会让我们更好地了解失忆症、成瘾症和其他神经系统疾病，这些疾病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.