Department of Occupational and Environmental Health, Dalian Medical University, Dalian, 116044, People's Republic of China.
Digestive Endoscopic Department of the second Hospital of Jilin University, Changchun, 130000, People's Republic of China.
Neurochem Res. 2018 Apr;43(4):948-958. doi: 10.1007/s11064-018-2500-4. Epub 2018 Feb 24.
Epidemiological investigations and experimental studies indicate that chronic arsenic exposure can reduce learning and memory function. However, the underlying mechanism of this effect remains largely unknown. Emerging evidence suggests that microRNA (miRNA) play an important role in toxicant exposure and a regulatory role in cognitive function. In this study, we observed that subchronic arsenic exposure induced impairment of learning and memory and significantly up-regulated miRNA-219 (miR-219) expression in the mouse hippocampus. Furthermore, the expression of CaMKII, an experimentally validated target of miR-219, was decreased in the mice exposed to arsenic. Suppression of miR-219 by adeno-associated viral (AAV)-delivered anti-miR-219 prevented the arsenic-induced impairment of learning and memory and relieved the pathological changes in the synaptic structure of the hippocampus. Furthermore, we observed that the NMDA receptor subunit 2 (NR2) and the memory-related proteins c-Fos and c-Jun were up-regulated by inhibition of miR-219 in the mouse hippocampus. Taken together, the results of this study indicate that inhibition of miR-219 regulates arsenic-induced damage in the structure of the hippocampus and impairment of learning and memory, possibly by targeting CaMKII. Suppression of miR-219 may be a potential strategy to ameliorate arsenic-induced neurotoxicity.
流行病学调查和实验研究表明，慢性砷暴露会降低学习和记忆功能。然而，这种效应的潜在机制在很大程度上仍然未知。新出现的证据表明，microRNA（miRNA）在毒物暴露中发挥重要作用，并在认知功能中起调节作用。在这项研究中，我们观察到亚慢性砷暴露会导致学习和记忆受损，并显著上调小鼠海马中的 miRNA-219（miR-219）表达。此外，砷暴露的小鼠中海马中 CaMKII 的表达减少，CaMKII 是 miR-219 的实验验证靶标。腺相关病毒（AAV）传递的抗 miR-219 抑制 miR-219 可防止砷诱导的学习和记忆损伤，并缓解海马突触结构的病理变化。此外，我们观察到 miR-219 的抑制可上调 NMDA 受体亚基 2（NR2）和与记忆相关的蛋白质 c-Fos 和 c-Jun，从而改善学习和记忆。综上所述，本研究结果表明，抑制 miR-219 可能通过靶向 CaMKII 调节砷诱导的海马结构损伤和学习记忆障碍。抑制 miR-219 可能是改善砷诱导神经毒性的一种潜在策略。
