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Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.
Nature Medicine ( IF 58.7 ) Pub Date : 2017-Nov-01 , DOI: 10.1038/nm.4413
Jason C You , Kavitha Muralidharan , Jin W Park , Iraklis Petrof , Mark S Pyfer , Brian F Corbett , John J LaFrancois , Yi Zheng , Xiaohong Zhang , Carrie A Mohila , Daniel Yoshor , Robert A Rissman , Eric J Nestler , Helen E Scharfman , Jeannie Chin

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.

中文翻译:

ΔFosB对海马calbindin-D28k的表观遗传抑制可导致癫痫发作相关的认知功能障碍。

钙结合蛋白calbindin-D28k对于海马功能和认知至关重要,但在与癫痫样活动和癫痫发作相关的各种神经系统疾病中其表达明显降低。在伴有反复发作的阿尔茨海默氏病(AD)和癫痫病中,认知缺陷的严重程度反映了海马齿状回(DG)中钙结合蛋白减少的程度。然而,尽管钙结合蛋白在神经元生理学和病理学中都具有重要意义,但对其在海马中表达的调控机制知之甚少。在这里,我们报告了一种表观遗传机制,癫痫发作可通过这种机制长期抑制海马calbindin的表达并削弱认知能力。我们证明了ΔFosB,一种高度稳定的转录因子,在AD和癫痫发作的小鼠模型中,海马诱导了海马蛋白的表达,其中它与calbindin基因(Calb1)的启动子结合并触发组蛋白去乙酰化,并下调Calb1的转录。值得注意的是,通过直接的病毒介导的表达或抑制ΔFosB信号来增加DG钙结合蛋白的水平,可以改善AD小鼠模型的空间记忆。此外,在患有颞叶癫痫(TLE)或AD的个体的DG中,ΔFosB和钙结合蛋白的表达水平呈负相关,并且与小精神状态检查(MMSE)的表现相关。我们提出,ΔFosB长期抑制钙结合蛋白是一种机制,通过这种机制,间歇性癫痫发作可在持续发作的情况下驱动持续的认知缺陷。它结合并触发calbindin基因(Calb1)启动子处的组蛋白去乙酰化,并下调Calb1转录。值得注意的是,通过直接的病毒介导的表达或抑制ΔFosB信号来增加DG钙结合蛋白的水平,可以改善AD小鼠模型的空间记忆。此外,在患有颞叶癫痫(TLE)或AD的个体的DG中,ΔFosB和钙结合蛋白的表达水平呈负相关,并且与小精神状态检查(MMSE)的表现相关。我们提出,ΔFosB长期抑制钙结合蛋白是一种机制,通过这种机制,间歇性癫痫发作可在持续发作的情况下驱动持续的认知缺陷。它结合并触发calbindin基因(Calb1)启动子处的组蛋白去乙酰化,并下调Calb1转录。值得注意的是,通过直接的病毒介导的表达或抑制ΔFosB信号来增加DG钙结合蛋白的水平,可以改善AD小鼠模型的空间记忆。此外,在患有颞叶癫痫(TLE)或AD的个体的DG中,ΔFosB和钙结合蛋白的表达水平呈负相关,并且与小精神状态检查(MMSE)的表现相关。我们提出,ΔFosB长期抑制钙结合蛋白是一种机制,通过这种机制,间歇性癫痫发作可在持续发作的情况下驱动持续的认知缺陷。通过直接病毒介导的表达或抑制ΔFosB信号传导,可改善AD小鼠模型的空间记忆。此外,在患有颞叶癫痫(TLE)或AD的个体的DG中,ΔFosB和钙结合蛋白的表达水平呈负相关,并且与小精神状态检查(MMSE)的表现相关。我们提出,ΔFosB长期抑制钙结合蛋白是一种机制,通过这种机制,间歇性癫痫发作可在持续发作的情况下驱动持续的认知缺陷。通过直接病毒介导的表达或抑制ΔFosB信号传导,可改善AD小鼠模型的空间记忆。此外,在患有颞叶癫痫(TLE)或AD的个体的DG中,ΔFosB和钙结合蛋白的表达水平呈负相关,并且与小精神状态检查(MMSE)的表现相关。我们提出,ΔFosB长期抑制钙结合蛋白是一种机制,通过这种机制,间歇性癫痫发作可在持续发作的情况下驱动持续的认知缺陷。
更新日期:2017-10-16
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