Hyperexcitability and epileptic seizures in a model of frontotemporal dementia
Hyperexcitability and epileptic seizures in a model of frontotemporal dementia
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DOI：
10.1016/j.nbd.2013.06.005
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发表时间：
2013-10-01
影响因子：
6.1
通讯作者：
Sanchez, Marina P.
中科院分区：
文献类型：
--
作者：
Garcia-Cabrero, Ana M.;Guerrero-Lopez, Rosa;Sanchez, Marina P.
癫痫发作在阿尔茨海默病患者中比在普通老年人群中更常见。异常形式的过度磷酸化tau在阿尔茨海默病和其他tauopy病中积累。在癫痫患者和癫痫的实验模型中也发现了tau的聚集。在这里，我们报告了过量表达人类突变体tau的转基因系癫痫活动和神经病理相关性的分析，tau是一种与17号染色体连锁的额颞部痴呆模型(FTDP-17)。与年龄匹配的对照组相比，FTDP-17模型表现出自发的癫痫活动和EEG中有棘波复合波的癫痫发作，并且对GABA(A)受体拮抗剂戊四氮(PTZ)的敏感性更高，表现出显著延长的癫痫发作长度和较短的形成严重癫痫的潜伏期。注射PTZ后，FTDP-17人tau突变体也表现出较低的惊厥阈值和较高的致死率。在这些结构中出现过度磷酸化的tau聚集体之前，星形胶质细胞和激活的小胶质细胞在幼年FTDP-17小鼠的海马区和其他表达人突变tau基因的脑区显著。在没有Aβ病理的情况下，FTDP-17人突变体tau的过度表达会导致癫痫和GABA(A)受体介导的过度兴奋性增加。虽然在癫痫患者和不同的化学和电产生的癫痫模型中观察到了过度磷酸化的tau聚集体，但这里分析的FTDP-17 tau突变体是第一个表现为癫痫的转基因tau模型。这个模型可能是一个有价值的工具，以测试新的治疗方法，以减少tau病理，一个潜在的因素，可能参与癫痫发作的痴呆和其他神经退行性疾病的发展。(C)2013 Elsevier Inc.保留所有权利。
Epileptic seizures are more common in patients with Alzheimer disease than in the general elderly population. Abnormal forms of hyperphosphorylated tau accumulate in Alzheimer disease and other tauopathies. Aggregates of tau are also found in patients with epilepsy and in experimental models of epilepsy. We report here the analysis of epileptic activity and neuropathological correlates of a transgenic line over-expressing human mutant tau, a model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The FTDP-17 model displays spontaneous epileptic activity and seizures with spike-wave complexes in the EEG, and a higher sensitivity to the GABA(A) receptor antagonist pentylenetetrazol (PTZ) when compared to age-matched controls, showing a notably increased seizure length and a shorter latency to develop severe seizures. FTDP-17 human tau mutants also display lower convulsive thresholds and higher lethality after PTZ injections. Astrocytosis and activated microglia are prominent in the hippocampus and other brain regions of young FTDP-17 mice where the human mutant tau transgene is expressed, before the appearance of hyperphosphorylated tau aggregates in these structures. FTDP-17 human mutant tau over-expression produces epilepsy and increased GABA(A) receptor-mediated hyperexcitability in the absence of A beta pathology. Although aggregates of hyperphosphorylated tau have been observed in patients with epilepsy and in different chemically and electrically generated models of epilepsy, the FTDP-17 tau mutant analyzed here is the first model of genetically modified tau that presents with epilepsy. This model may represent a valuable tool to assay novel treatments in order to reduce tau pathology, a potential factor which may be involved in the development of epileptic seizures in dementia and other neurodegenerative diseases. (C) 2013 Elsevier Inc. All rights reserved.