miR-124, a brain-specific microRNA, was originally considered as a key regulator in neuronal differentiation and the development of the nervous system. Here we showed that miR-124 expression was suppressed in patients with epilepsy and rats after drug induced-seizures. Intrahippocampal administration of a miR-124 duplex led to alleviated seizure severity and prolonged onset latency in two rat models (pentylenetetrazole- and pilocarpine-induced seizures), while miR-124 inhibitor led to shortened onset latency in pilocarpine-induced seizure rat models. Moreover, the result of local field potentials (LFPs) records further demonstrated miR-124 may have anti-epilepsy function. Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR. In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3′UTR of CREB1 gene and repressed the CREB1 expression in HEK293T cells. Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus. These results revealed a previously unknown function of miR-124 in neuronal excitability and provided a new insight into molecular mechanisms underlying epilepsy.

中文翻译：

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microRNA miR-124 抑制癫痫发作并调节 CREB1 活性


miR-124是一种大脑特异性的microRNA，最初被认为是神经元分化和神经系统发育的关键调节因子。在这里，我们发现癫痫患者和药物诱导癫痫发作后的大鼠中 miR-124 的表达受到抑制。在两种大鼠模型（戊四唑和毛果芸香碱诱导的癫痫发作）中，海马内给予 miR-124 双链体可减轻癫痫发作的严重程度并延长发作潜伏期，而 miR-124 抑制剂可缩短毛果芸香碱诱导的癫痫发作大鼠模型的发作潜伏期。此外，局部场电位（LFP）记录的结果进一步证明miR-124可能具有抗癫痫功能。 miR-124 对神经元放电的抑制与 mEPSC、AMPAR 和 NMDAR 介导的电流的抑制有关，并伴有 NMDAR 表面表达的减少。此外，注射 miR-124 会导致 cAMP 反应元件结合蛋白 1 (CREB1) 的活性和表达降低。癫痫发生的关键调节因子。双荧光素酶报告基因检测证实miR-124直接靶向CREB1基因的3'UTR并抑制HEK293T细胞中CREB1的表达。免疫沉淀研究证实，CREB1 抗体可有效沉淀大鼠大脑海马中的 CREB1 和 NMDAR1，但不能沉淀 GLUR1。这些结果揭示了 miR-124 在神经元兴奋性中以前未知的功能，并为癫痫潜在的分子机制提供了新的见解。