Role of deltaFosB in epigenetic regulation of gene expression and cognition

描述（由申请人提供）：认知障碍是癫痫的一种毁灭性合并症。然而，反复发作诱发认知障碍的分子机制，即使在无发作期也持续存在，尚不清楚。这方面的知识差距阻碍了治疗性干预措施的发展，以减少与癫痫相关的认知缺陷。我们的初步研究表明，癫痫引起的海马转录因子FosB表达的增加触发了一系列事件，导致海马中许多基因的表观遗传抑制，其中一些已知对突触可塑性的诱导至关重要。癫痫发作严重程度的增加导致FosB的表达增加，这对基因表达产生了持久的表观遗传抑制，对海马依赖的空间记忆产生了有害的影响。在癫痫的药理学模型和阿尔茨海默病（AD）的转基因小鼠模型中观察到FosB表达的增加、表观遗传改变和相关的空间记忆缺陷，这两种疾病都表现为反复发作。本研究的目的是确定FosB诱导突触可塑性所需关键基因表观遗传抑制的机制，以及基因表达正常化是否能恢复复发性癫痫发作的kainate和AD模型的认知功能。为了实现这些目标，在Aim 1中，我们将研究不同癫痫发作严重程度的kainate和AD小鼠中FosB的表达谱和认知缺陷的严重程度；我们还将确定过度表达FosB是否足以诱导认知缺陷。在Aim 2中，我们将确定FosB诱导染色质修饰的机制，从而调节海钠酸盐和AD小鼠的基因表达。在Aim 3中，我们将确定一种显性FosB负拮抗剂的病毒表达是否会阻断FosB对海马基因表达的影响，并恢复kainate和AD小鼠的认知功能。这些研究的结果将为理解复发性癫痫发作如何损害认知功能开辟一条新的途径，并为靶向治疗提供一条新的途径。此外，它们将为与复发性癫痫发作（如AD）相关的任何疾病的认知障碍的共同机制提供新的见解。鉴于癫痫是许多神经系统疾病的合并症，我们的研究结果将产生广泛的影响。

DESCRIPTION (provided by applicant): Cognitive impairment is a devastating co-morbidity of epilepsy. However, the molecular mechanisms by which recurrent seizures induce cognitive impairments that persist even in seizure-free periods are not well understood. This gap in knowledge hampers the development of therapeutic interventions to reduce cognitive deficits associated with epilepsy. Our preliminary studies demonstrate that seizure-induced increase in hippocampal expression of the transcription factor �FosB triggers a chain of events leading to epigenetic repression of a number of genes in the hippocampus, some of which are known to be critical for the induction of synaptic plasticity. Increasing seizure severity led to increasing expression of �FosB that exerted long lasting epigenetic repression of gene expression, with detrimental consequences for hippocampal-dependent spatial memory. Such increases in �FosB expression, epigenetic alterations, and associated spatial memory deficits were observed in a pharmacological kainate model of epilepsy as well as a transgenic mouse model of Alzheimer's disease (AD), both of which exhibit recurrent seizures. The goals of this proposal are to determine the mechanisms by which �FosB induces epigenetic repression of key genes required for synaptic plasticity, and whether normalizing gene expression restores cognitive function in kainate and AD models with recurrent seizures. To achieve these goals, in Aim 1 we will investigate the expression profiles of �FosB expression and severity of cognitive deficits in kainate and AD mice with varying seizure severity; we will also determine whether overexpression of �FosB is sufficient to induce cognitive deficits. In Aim 2, we will identify the mechanisms by which �FosB induces chromatin modifications that regulate gene expression in kainate and AD mice. In Aim 3, we will determine whether viral expression of a dominant negative antagonist of �FosB blocks �FosB's effects on gene expression in the hippocampus, and restores cognitive function in kainate and AD mice. Results from these studies will forge a new avenue of understanding how recurrent seizures impair cognitive function, and highlight a novel pathway for therapeutic targeting. In addition, they will provide novel insights into common mechanisms of cognitive impairment in any condition associated with recurrent seizures, such as AD. Given that epilepsy is a co-morbidity of a number of neurological conditions/diseases the results from our studies will have broad impact.