Epigenetic Regulation of Hippocampal Synaptic Plasticity

描述(申请人提供)：长期记忆的巩固和长期突触增强的形成都需要基因转录和从头合成蛋白质。多个系统调节这些转录事件，提供对学习过程的几个控制点。我们和其他实验室最近的工作证明了表观遗传机制在学习和可塑性中的关键作用，这项工作揭示了表观遗传控制中断和认知障碍之间的联系。抑制组蛋白脱乙酰酶(HDAC)酶可增强正常记忆，并挽救疾病小鼠模型的记忆损害。尽管这种对转录的表观遗传调控的操纵显示出作为一种治疗工具的前景，但其功能的潜在机制尚不清楚。Sin3a是一种共抑制蛋白，它将HDAC酶招募到基因启动子中，通过组蛋白低乙酰化来维持它们的抑制。核受体亚家族4(Nr4a)转录因子通过组蛋白乙酰化由环AMP反应元件结合蛋白(CREB)和共激活因子CREB结合蛋白(CBP)调节，也是Sin3a/HDAC复合体负调控的强烈候选者。Nr4a家族的即刻早期基因在神经元激活后立即转录，已知Nr4A蛋白调节许多对记忆和可塑性重要的基因的转录。我建议在这里同时研究Sin3a和Nr4a转录的作用 海马区突触可塑性的影响因素及其调控靶点的识别 在海马体基因组中。 与公共健康相关：调节可塑性的机制的破坏，无论是通过遗传疾病、神经退行性疾病还是衰老，都会损害神经元功能和认知能力。了解通过表观遗传途径对学习和记忆的控制可以为此类疾病提供新的治疗方法。通过这里提出的实验，我希望了解海马区突触可塑性是如何由表观遗传机制调节的，以及这些途径如何可以用于治疗神经元功能障碍。。

DESCRIPTION (provided by applicant): The consolidation of long-term memory and the formation of long-term synaptic potentiation both require gene transcription and de novo protein synthesis. Multiple systems regulate these transcriptional events, offering several points of control over learning processes. Recent work from our lab and others has demonstrated a crucial role for epigenetic mechanisms in learning and plasticity, and this work has revealed links between disruption of epigenetic control and disorders of cognition. Inhibiting histone deacetylase (HDAC) enzymes enhances normal memory and rescue impairments of memory in mouse models of disease. Although this manipulation of the epigenetic regulation of transcription shows promise as a therapeutic tool, the underlying mechanisms of how it functions are unknown. Sin3a is a co-repressor protein that recruits HDAC enzymes to gene promoters to maintain their repression through histone hypoacetylation. The nuclear receptor subfamily 4 (Nr4a) transcription factors, regulated via histone acetylation by the cyclic AMP response element binding protein (CREB) and the co-activator CREB-binding protein (CBP), are also strong candidates for negative regulation by the Sin3a/HDAC complex. The Nr4a family of immediate early genes is transcribed immediately after neuronal activation, and the NR4A proteins are known to regulate the transcription of many genes important for memory and plasticity. I propose here to investigate in parallel the roles of Sin3a and the Nr4a transcription factors in hippocampal synaptic plasticity, and to uncover the identity of their regulatory targets in the hippocampal genome. PUBLIC HEALTH RELEVANCE: Disruption of the machinery regulating plasticity, whether it is through a genetic disorder, neurodegenerative disease, or aging, impairs neuronal function and cognitive ability. Understanding the control of learning and memory through epigenetic pathways could offer novel therapeutic approaches to such disorders. Through the experiments proposed here, I hope to understand how hippocampal synaptic plasticity is regulated by epigenetic mechanisms, and how these pathways can be used to treat neuronal dysfunction. .