The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.

中文翻译：

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一种基于一氧化氮供体的新型颞叶癫痫抗癫痫发生策略。


海马肺门中间神经元变性在颞叶癫痫 （TLE） 中作用的分子机制尚不清楚。特别是，很少有研究关注含有肺门中间神经元的神经元一氧化氮合酶 （nNOS，由 Nos1 编码） 在 TLE 中的作用。在本研究中，构建了 Nos1 条件性敲除小鼠，我们发现肺门中间神经元中 Nos1 的选择性缺失而不是齿状颗粒细胞 （DGC） 触发了癫痫发生。TLE 患者和小鼠的 nNOS 水平下调。Nos1 缺失导致过度癫痫样兴奋性输入电路形成和 DGC 的过度兴奋。肺门 nNOS 蛋白的补充阻断了毛果芸香碱诱导的 TLE 小鼠的致癫痫发展和记忆障碍。此外，用缓慢释放的外源性一氧化氮 （NO） 供体 DETA/NONOate 进行长期治疗，防止了 DGC 的异常神经回路和随之而来的癫痫发生，而没有急性抗癫痫作用。因此，我们得出结论，NO 供体治疗可能是一种新型的抗癫痫发生策略，不同于现有的抗癫痫药物 （ASMs），用于治疗 TLE。