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的共同发病。然而，反复发作导致认知损害的分子机制还不是很清楚，即使在无发作的时期也是如此。这种知识上的差距阻碍了减少与癫痫相关的认知缺陷的治疗干预措施的发展。我们的初步研究表明，癫痫发作诱导的海马区转录因子�FosB的表达增加触发了一系列事件，导致海马区一些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，从而对基因表达施加持久的表观遗传抑制，从而对海马区依赖的空间记忆造成不利后果。在癫痫的药理红藻氨酸模型和阿尔茨海默病(AD)的转基因小鼠模型中观察到了�FosB表达的增加、表观遗传学改变和相关的空间记忆缺陷，这两种模型都表现出反复发作。该方案的目的是确定�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能恢复反复发作的Kainate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�FosB在不同严重程度的海人酸和AD小鼠中的表达情况和认知障碍的严重程度；我们还将确定�FosB的过度表达是否足以导致认知障碍。在目标2中，我们将确定�FosB诱导染色质修饰的机制，该修饰调节Kainate和AD小鼠的基因表达。在目标3中，我们将确定病毒表达�FosB的显性负性拮抗剂是否能阻断�FosB对海马区基因表达的影响，并恢复Kainate和AD小鼠的认知功能。这些研究的结果将为理解反复发作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，在任何与反复发作相关的条件下，如阿尔茨海默病，认知障碍的常见机制。鉴于癫痫是多种神经疾病/疾病的共同发病，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.