Role of deltaFosB in hippocampal gene expression and function in neurological disease

deltaFosB 在神经系统疾病中海马基因表达和功能中的作用

• 批准号: 10189710
• 负责人: JEANNIE CHIN
• 金额: $ 59.46万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189710
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Benchmarking; Biochemical; Biological; Brain; Calcium; Cells; ChIP-seq; Chloride Channels; Chromatin; Cognition; Cognitive deficits; Data; Dominant-Negative Mutation; Epigenetic Process; Epilepsy; Epileptogenesis; Exhibits; Gene Expression; Gene Targeting; Genes; Goals; Hippocampus (Brain); Impaired cognition; Intervention; Lead; Longevity; Mediating; Memory; Memory Loss; Modeling; Molecular; Motor Seizures; Mus; National Institute of Neurological Disorders and Stroke; Neurologic; Neurons; Pathologic; Pathway Analysis; Patients; Pharmacology; Phenotype; Pilocarpine; Play; Publishing; Recurrence; Regulation; Research; Role; Seizures; Signal Transduction; Specific qualifier value; Synaptic plasticity; Testing; Therapeutic; Transgenic Mice; Viral; Wild Type Mouse; Work; adverse outcome; cognitive function; comorbidity; cost; dentate gyrus; gene function; improved; mouse model; nervous system disorder; neuronal excitability; novel; novel strategies; novel therapeutic intervention; overexpression; prevent; programs; public health relevance; theories; therapy design; transcription factor

Project Summary Cognitive impairment is a devastating co-morbidity of conditions with recurrent seizures, such as Alzheimer's disease and epilepsy, which persists even in seizure-free periods. We recently published that one critical reason for this is that seizures induce dentate gyrus (DG) expression of ∆FosB, a transcription factor that epigenetically suppresses key target genes that are crucial for plasticity and memory. ∆FosB expression is associated with cognitive deficits in patients and mouse models of epilepsy as well as Alzheimer's disease, demonstrating common mechanisms of cognitive dysfunction in conditions with seizures. Our new studies indicate ∆FosB acts on more than memory-related genes; it also represses genes that enhance intrinsic excitability, and thereby limits overall DG excitability. These findings indicate that seizure-induced ∆FosB expression is a “double-edged sword” that caps DG excitability, but at the cost of plasticity and cognitive function. Our goals are to build a comprehensive understanding of functional domains regulated by ∆FosB in the hippocampus, and identify novel strategies to improve cognition but maintain regulation of neuronal excitability in conditions with seizures, such as Alzheimer's disease and epilepsy. We previously used hypothesis-driven approaches to identify ∆FosB targets in hippocampus, but it was necessary to also obtain an unbiased, comprehensive view of ∆FosB in seizure-related conditions. To do so, we performed ChIP- sequencing to identify all genes bound by ∆FosB in the hippocampus of a well-characterized transgenic mouse model of Alzheimer's disease (AD mice) that exhibits recurrent seizures and high ∆FosB levels. In AD mice, ∆FosB bound to a novel network of genes involved in multiple aspects of neuronal excitability. Many of these genes were also bound by ∆FosB in hippocampus of wild-type mice treated with pilocarpine, a pharmacological model of epilepsy. In wild-type mice, AAV-mediated overexpression of ∆FosB decreased excitability whereas ∆JunD, a dominant negative antagonist of ∆FosB, increased excitability. Notably, long- term blockade of ∆FosB signaling in DG of AD mice changed the phenotype of their seizures from primarily nonconvulsive to primarily convulsive, supporting the theory that the typically low excitability and sparse activation of DG cells acts as a filter or gate that restricts epileptogenesis. Our work indicates ∆FosB plays critical roles in neuronal function in conditions with recurrent seizures. Understanding the mechanisms by which ∆FosB coordinately regulates expression of genes that control synaptic plasticity or neuronal excitability may reveal novel therapeutic strategies to reduce epileptogenesis while improving cognition. To this end, we will examine both Alzheimer's mice and pilocarpine mice to: 1) Investigate the role of ∆FosB in controlling intrinsic and network excitability of the DG, 2) identify and characterize the repertoire of hippocampal genes targeted by ∆FosB to control excitability, and 3) test whether specific ∆FosB target genes are key determinants of DG excitability and cognition.

项目摘要 认知障碍是与复发性癫痫发作的灾难性的合并症，例如阿尔茨海默氏症 疾病和癫痫病，即使在无癫痫发作的时期也存在。我们最近发表了一个关键 原因是癫痫发作会影响∆FOSB的齿状回（DG）表达，这是转录因子 表观遗传抑制对可塑性和记忆至关重要的关键靶基因。 ∆FOSB表达为 与认知能力相关的癫痫患者和小鼠模型以及阿尔茨海默氏病的小鼠模型相关， 证明在癫痫发作的条件下认知功能障碍的常见机制。我们的新研究 表明∆FOSB对与记忆相关的基因的作用更多。它还反映了增强内在的基因 兴奋性，从而限制了总体DG兴奋性。这些发现表明癫痫发作引起的∆FOSB 表达是一把“双刃剑”，令人兴奋的DG令人兴奋，但以可塑性和认知为代价 功能。我们的目标是对由∆FOSB监管的功能领域建立全面的理解 海马，并确定改善认知但保持神经元调节的新型策略 癫痫发作的兴奋性，例如阿尔茨海默氏病和癫痫。我们以前使用过 假设驱动的方法以鉴定海马中的∆FOSB靶标，但也有必要获得 在癫痫发作相关条件下ΔFOSB的公正，全面的视图。为此，我们进行了芯片 - 测序以识别在特征良好的转基因小鼠的海马中由∆FOSB结合的所有基因 阿尔茨海默氏病（AD小鼠）的模型，该模型表现出复发性癫痫发作和高∆FOSB水平。在AD小鼠中， ∆FOSB与一个新的基因网络结合在一起，涉及神经元令人兴奋的多个方面。其中许多 基因也由胰岛pilocarpine治疗的野生型小鼠海马中的∆FOSB结合 癫痫的药理模型。在野生型小鼠中，AAV介导的∆FOSB的过表达降低 令人兴奋的是，∆FOSB的主要负拮抗剂∆Jund增加了令人兴奋的。值得注意的是，长期 AD小鼠DG中∆FOSB信号传导的术语封锁改变了其原发性癫痫发作的表型 对原发性抽搐的敏感性，支持通常低刺激性和稀疏性的理论 DG细胞的激活充当限制癫痫发生的过滤器或栅极。我们的工作表明∆FOSB戏剧 在复发性癫痫发作的条件下，神经元功能中的关键作用。了解机制 ∆FOSB协调调节控制突触可塑性或神经元刺激性的基因的表达 可能揭示了在改善认知时减少癫痫发生的新型热策略。为此，我们 将检查阿尔茨海默氏症的小鼠和毛果皮小鼠：1）研究∆FOSB在控制中的作用 DG的内在和网络令人兴奋，2）识别和表征海马基因的曲目 由∆FOSB靶向控制兴奋性，3）测试特定的∆FOSB目标基因是否为关键确定剂 DG兴奋性和认知。