Seizure incidence is increased in Alzheimer’s disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of ΔFosB, a transcription factor with a long half-life. Even the infrequent seizures that spontaneously occur in transgenic mice expressing human amyloid precursor protein (APP) lead to persistent increases in ΔFosB in the hippocampus, similar to what we observed in patients with AD or temporal lobe epilepsy. ΔFosB epigenetically regulates expression of target genes, however, whether ΔFosB targets the same genes when induced by seizures in different neurological conditions is not clear. We performed ChIP-sequencing to assess the repertoire of ΔFosB target genes in APP mice and in pilocarpine-treated wildtype mice (Pilo mice), a pharmacological model of epilepsy. These mouse models allowed us to compare AD, in which seizures occur in the context of high levels of amyloid beta, and epilepsy, in which recurrent seizures occur without AD-specific pathophysiology. Network profiling of genes bound by ΔFosB in APP mice, Pilo mice, and respective control mice revealed that functional domains modulated by ΔFosB in the hippocampus are expanded and diversified in APP and Pilo mice (vs. respective controls). Domains of interest in both disease contexts involved neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and neuroinflammation. To assess the gene targets bound by ΔFosB regardless of seizure etiology, we focused on 442 genes with significant ΔFosB binding in both APP and Pilo mice (vs. respective controls). Functional analyses identified pathways that regulate membrane potential, glutamatergic signaling, calcium homeostasis, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and qPCR measurements in independent mice detected altered expression of several ΔFosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced ΔFosB can bind genes in patterns that depend on seizure etiology, but can bind other genes regardless of seizure etiology. Understanding the factors that underlie these differences, such as chromatin accessibility and/or abundance of co-factors, could reveal novel insights into the control of gene expression in disorders with recurrent seizures.

中文翻译：

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ΔFosB 在不同条件下与复发性癫痫发作结合的基因调节类似的神经元功能

阿尔茨海默病 (AD) 患者和小鼠模型的癫痫发作率增加，抗癫痫药物左乙拉西坦治疗可改善认知。我们报告说，癫痫发作对认知产生持续影响的一种机制是通过 ΔFosB 的积累，ΔFosB 是一种半衰期长的转录因子。即使在表达人淀粉样前体蛋白 (APP) 的转基因小鼠中自发发生的罕见癫痫也会导致海马中 ΔFosB 的持续增加，类似于我们在 AD 或颞叶癫痫患者中观察到的情况。ΔFosB 表观遗传调节靶基因的表达，然而，当不同神经系统疾病的癫痫发作诱导时，ΔFosB 是否靶向相同基因尚不清楚。我们进行了 ChIP 测序以评估 APP 小鼠和毛果芸香碱治疗的野生型小鼠（Pilo 小鼠）（一种癫痫药理学模型）中 ΔFosB 靶基因的所有组成部分。这些小鼠模型使我们能够比较 AD（癫痫发作发生在高水平的淀粉样蛋白 β 的背景下）和癫痫（癫痫发作在没有 AD 特异性病理生理学的情况下发生）。APP 小鼠、Pilo 小鼠和各自对照小鼠中由 ΔFosB 结合的基因的网络分析显示，海马中由 ΔFosB 调节的功能域在 APP 和 Pilo 小鼠中得到扩展和多样化（与各自的对照相比）。在这两种疾病背景下感兴趣的领域都涉及神经元兴奋性和神经传递、神经发生、染色质重塑以及细胞应激和神经炎症。为了评估由 ΔFosB 结合的基因靶标，而不管癫痫发作的病因如何，我们重点研究了 442 个在 APP 和 Pilo 小鼠中具有显着 ΔFosB 结合的基因（相对​​于各自的对照）。功能分析确定了调节膜电位、谷氨酸能信号、钙稳态、补体激活、神经元-胶质细胞群维持和染色质动力学的途径。独立小鼠的 RNA 测序和 qPCR 测量检测到 APP 和 Pilo 小鼠共享的几个 ΔFosB 靶标的表达改变。我们的研究结果表明，癫痫诱发的 ΔFosB 可以以取决于癫痫病因的模式结合基因，但无论癫痫病因如何，都可以结合其他基因。了解造成这些差异的因素，例如染色质的可及性和/或辅因子的丰度，