Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.
Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.
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DOI：
10.1038/nm.4413
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发表时间：
2017-11
期刊：
影响因子：
82.9
通讯作者：
Chin J
中科院分区：
文献类型：
--
作者：
You JC;Muralidharan K;Park JW;Petrof I;Pyfer MS;Corbett BF;LaFrancois JJ;Zheng Y;Zhang X;Mohila CA;Yoshor D;Rissman RA;Nestler EJ;Scharfman HE;Chin J
钙结合蛋白calbindin-D28 k对海马功能和认知至关重要，但其表达在与癫痫样活动和癫痫发作相关的各种神经系统疾病中显著降低。在阿尔茨海默病（AD）和癫痫，这两者都伴随着反复发作，认知功能障碍的严重程度反映了海马齿状回（DG）的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的重要性，但控制其在海马中表达的调节机制知之甚少。在这里，我们报告了癫痫发作慢性抑制海马钙结合蛋白表达和损害认知的表观遗传机制。我们证明，ΔFosB是一种高度稳定的转录因子，在AD和癫痫发作小鼠模型的海马中被诱导，在那里它结合并触发钙结合蛋白基因（Calb 1）启动子处的组蛋白脱乙酰化，并下调Calb 1转录。值得注意的是，通过直接病毒介导的表达或抑制ΔFosB信号传导来增加DG钙结合蛋白水平，可以改善AD小鼠模型的空间记忆。此外，ΔFosB和钙结合蛋白表达水平在颞叶癫痫（TLE）或AD患者的DG中呈负相关，并与简易精神状态检查（MMSE）的表现相关。我们认为ΔFosB对钙结合蛋白的慢性抑制是间歇性癫痫发作在伴有复发性癫痫发作的情况下驱动持续性认知缺陷的一种机制。
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 by which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus of mouse models of AD and seizures, where it binds and triggers histone deacetylation at the calbindin gene (Calb1) promoter, 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 DG of patients 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 by which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.
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影响因子：
4.7
作者：
Jouvenceau, A;Potier, B;Billard, JM
通讯作者：
Billard, JM
DOI：
10.1073/pnas.93.15.8028
发表时间：
1996-07-23
影响因子：
11.1
作者：
Molinari, S;Battini, R;Emson, PC
通讯作者：
Emson, PC
影响因子：
6.1
作者：
Lopez-Meraz ML;Wasterlain CG;Rocha LL;Allen S;Niquet J
通讯作者：
Niquet J
影响因子：
3.3
作者：
Klapstein, GJ;Vietla, S;Mody, I
通讯作者：
Mody, I
影响因子：
2.2
作者：
Carter, Dawn S.;Harrison, Anne J.;DeLorenzo, Robert J.
通讯作者：
DeLorenzo, Robert J.