QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
Sci Rep. 2017 Jan 5;7:40127. doi: 10.1038/srep40127.
Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy.
尽管长链非编码 RNA 在哺乳动物神经系统中大量存在，但它们的分子功能仍知之甚少。本文表明，长链非编码 RNA NEAT1 可直接调节神经元兴奋性，并与病理性癫痫发作状态有关。具体而言，NEAT1 在体外和体内受神经元活动的动态调节，与癫痫相关的钾通道相互作用蛋白（包括 KCNAB2 和 KCNIP1）结合，并在反义寡核苷酸敲低后诱导 iPSC 衍生的人类皮质神经元产生神经元超极化表型。下一代测序显示，在通过 NEAT1 敲低激活 iPSC 衍生神经元后，NEAT1 与离子通道基因表达的增加有很强的关联。此外，我们还表明，虽然神经元活动会导致 NEAT1 急性下调，但在与颞叶癫痫相关的独立体内大鼠模型系统中，重复刺激会导致 NEAT1 慢性无反应。我们扩展了先前的研究结果，表明在难治性癫痫患者皮质组织的高尖峰区域中，NEAT1 的表达增加。我们的研究结果表明 NEAT1 在调节人类神经元活动中的作用，并提示一种活性依赖性长链非编码 RNA 与癫痫之间的新的机制联系。
