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并发症。然而，复发性癫痫发作诱导认知障碍的分子机制，即使在无癫痫发作期间也持续存在，尚未得到很好的理解。这种知识的差距阻碍了治疗干预措施的发展，以减少与癫痫相关的认知缺陷。我们的初步研究表明，海马转录因子FosB表达的增加引发了一系列事件，导致海马中许多基因的表观遗传抑制，其中一些已知对诱导突触可塑性至关重要。癫痫发作严重程度的增加导致FosB表达的增加，FosB对基因表达产生长期的表观遗传抑制，对大脑依赖的空间记忆产生不利影响。在癫痫的药理学红藻氨酸盐模型以及阿尔茨海默病（AD）的转基因小鼠模型中观察到了FosB表达，表观遗传改变和相关的空间记忆缺陷的增加，这两种模型都表现出复发性癫痫。该提案的目标是确定FosB诱导突触可塑性所需关键基因的表观遗传抑制的机制，以及正常化基因表达是否恢复了海人酸盐和AD模型的认知功能。为了实现这些目标，在目标1中，我们将研究不同癫痫严重程度的红藻氨酸和AD小鼠中fosB表达的表达谱和认知缺陷的严重程度;我们还将确定fosB的过表达是否足以诱导认知缺陷。在目标2中，我们将确定FosB诱导染色质修饰的机制，这些修饰调节红藻氨酸和AD小鼠的基因表达。在目标3中，我们将确定显性负性拮抗剂FosB的病毒表达是否阻断FosB对海马基因表达的影响，并恢复红藻氨酸和AD小鼠的认知功能。这些研究的结果将为理解复发性癫痫如何损害认知功能开辟一条新的途径，并为治疗靶向开辟一条新的途径。此外，他们将提供新的见解认知障碍的常见机制，在任何条件下与复发性癫痫发作，如AD。鉴于癫痫是许多神经系统疾病的共病，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.