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Hyperexcitability and epileptic seizures in a model of frontotemporal dementia

机译：额颞痴呆模型中的过度兴奋和癫痫发作

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摘要

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 GABAA 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 GABAA receptor-mediated hyperexcitability in the absence of Aβ 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.
机译：阿尔茨海默病患者的癫痫发作比普通老年人更为常见。高磷酸化tau蛋白的异常形式在阿尔茨海默氏病和其他疾病中积累。在患有癫痫的患者和癫痫的实验模型中也发现了tau的聚集体。我们在这里报告的过度表达人类突变体tau，一种额颞痴呆模型，与17号染色​​体（FTDP-17）相关的帕金森病的癫痫活动和神经病理学相关性的分析。 FTDP-17模型显示自发性癫痫活动和脑电图中带有尖峰波复合物的癫痫发作，与年龄相匹配的对照组相比，对GABAA受体拮抗剂戊四氮（PTZ）的敏感性更高，显示癫痫发作时间明显增加，发作时间更短发生严重癫痫的潜伏期。 FTDP-17人tau突变体在注射PTZ后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磷酸化的tau聚集体之前，在表达人突变tau转基因的年轻FTDP-17小鼠的海马和其他大脑区域中，星形胶质细胞增多和活化的小胶质细胞突出。在没有Aβ病理学的情况下，FTDP-17人突变体tau的过表达导致癫痫和GABAA受体介导的过度兴奋性增加。尽管在癫痫患者以及在不同的化学和电产生的癫痫模型中均观察到了高磷酸化tau的聚集体，但此处分析的FTDP-17 tau突变体是第一个出现癫痫的转基因tau模型。该模型可能代表了一种测定新疗法以减少tau病理的有价值的工具，tau病理可能是痴呆症和其他神经退行性疾病的癫痫发作发展的潜在因素。

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