Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy.
Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy.
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DOI：
10.1523/jneurosci.3191-12.2013
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发表时间：
2013-01-23
期刊：
影响因子：
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通讯作者：
Noebels JL
中科院分区：
文献类型：
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作者：
Holth JK;Bomben VC;Reed JG;Inoue T;Younkin L;Younkin SG;Pautler RG;Botas J;Noebels JL
神经元网络的超兴奋性是癫痫发病的基础，也是阿尔茨海默病(AD)等退行性神经系统疾病的组成部分。最近，微管结合蛋白tau参与了网络同步化的调节。在过度表达淀粉样β蛋白(Aβ)的AD模型中，基因移除编码tau的MAPT可降低过度兴奋性，并使兴奋/抑制失衡正常化。这种去除tau的效果是否仅限于Aβ小鼠模型仍有待确定。在这里，我们在小鼠和果蝇的高兴奋性模型中使用tau的基因缺失来研究tau作为非AD神经系统的兴奋性修饰物。KcNA1−/−小鼠缺乏Kv1.1延迟整流电流，表现出严重的自发性癫痫发作、早期死亡和巨脑。年轻的KcnA1−/−小鼠保持了野生型Aβ、tau和tau磷酸化-Thr231的水平。降低kcna1−/−小鼠的tau降低了过度兴奋性并缓解了与癫痫相关的合并症。Tau减少可降低KcNA1−/−视频脑电记录的癫痫发作频率和持续时间，并使KcNA1−/−海马网的超兴奋性正常化。此外，核磁共振显示，tau的减少增加了kcna1−/−的存活率，并防止了巨脑和海马体肥大。Bang敏感的果蝇突变体对机械刺激的反应表现为瘫痪和癫痫发作，为上位性相互作用提供了补充的兴奋性分析。我们发现，在两个独立的Bang敏感突变模型KCC和EAS中，tau的降低显著降低了癫痫发作的敏感性。我们的结果表明，tau在调节固有的神经元网络超兴奋性方面起着普遍的作用，而不是依赖于Aβ的过度表达，并提示降低tau功能可能是癫痫障碍和抗癫痫治疗干预的一个可行的靶点。
Neuronal network hyperexcitability underlies the pathogenesis of seizures and is a component of some degenerative neurological disorders such as Alzheimer’s disease (AD). Recently, the microtubule binding protein tau has been implicated in the regulation of network synchronization. Genetic removal of Mapt, the gene encoding tau, in AD models overexpressing amyloid-beta (Aβ) decreases hyperexcitability and normalizes the excitation/inhibition imbalance. Whether this effect of tau removal is specific to Aβ mouse models remains to be determined. Here we examined tau as an excitability modifier in the non-AD nervous system using genetic deletion of tau in mouse and Drosophila models of hyperexcitability. Kcna1−/− mice lack Kv1.1 delayed rectifier currents and exhibit severe spontaneous seizures, early lethality, and megencephaly. Young Kcna1−/− mice retained wild-type levels of Aβ, tau, and tau phospho-Thr231. Decreasing tau in Kcna1−/− mice reduced hyperexcitability and alleviated seizure-related comorbidities. Tau reduction decreased Kcna1−/− video-EEG recorded seizure frequency and duration as well as normalized Kcna1−/− hippocampal network hyperexcitability in vitro. Additionally, tau reduction increased Kcna1−/− survival and prevented megencephaly and hippocampal hypertrophy, as determined by MRI. Bang-sensitive Drosophila mutants display paralysis and seizures in response to mechanical stimulation, providing a complementary excitability assay for epistatic interactions. We found that tau reduction significantly decreased seizure sensitivity in two independent bang-sensitive mutant models, kcc and eas. Our results indicate that tau plays a general role in regulating intrinsic neuronal network hyperexcitability independently of Aβ overexpression and suggest that reducing tau function could be a viable target for therapeutic intervention in seizure disorders and antiepileptogenesis.