Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Neurosci. 2013 Jan 23;33(4):1651-9. doi: 10.1523/JNEUROSCI.3191-12.2013.
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-β (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-Thr(231). 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.
神经网络过度兴奋是癫痫发病机制的基础，也是某些退行性神经疾病的组成部分，如阿尔茨海默病（AD）。最近，微管结合蛋白 tau 被认为参与了网络同步的调节。在过度表达淀粉样蛋白-β（Aβ）的 AD 模型中，遗传去除编码 tau 的 Mapt 基因可降低过度兴奋并使兴奋/抑制失衡正常化。tau 去除的这种作用是否特定于 Aβ 小鼠模型仍有待确定。在这里，我们使用tau 在过度兴奋的小鼠和果蝇模型中的兴奋性调节剂，通过基因敲除 tau 来研究非 AD 神经系统中的 tau。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、早期死亡和巨脑症。年轻的 Kcna1（-/-）小鼠保留了野生型水平的 Aβ、tau 和 tau 磷酸化-Thr（231）。在 Kcna1（-/-）小鼠中降低 tau 可降低过度兴奋并减轻与癫痫相关的合并症。tau 减少降低了 Kcna1（-/-）视频-EEG 记录的癫痫发作频率和持续时间，以及体外正常化 Kcna1（-/-）海马网络过度兴奋。此外，tau 减少增加了 Kcna1（-/-）的存活率，并通过 MRI 预防了巨脑症和海马体肥大。Bang 敏感型果蝇突变体对机械刺激表现出瘫痪和癫痫发作，为遗传相互作用提供了互补的兴奋性测定。我们发现，在两个独立的 Bang 敏感突变模型 kcc 和 eas 中，tau 减少显著降低了癫痫发作的敏感性。我们的结果表明，tau 独立于 Aβ 过表达在调节内在神经元网络过度兴奋中起着一般作用，并表明降低 tau 功能可能是治疗癫痫发作和抗癫痫形成的可行靶点。
