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Lrp4 in hippocampal astrocytes serves as a negative feedback factor in seizures
Cell and Bioscience ( IF 7.5 ) Pub Date : 2020-11-23 , DOI: 10.1186/s13578-020-00498-w
Zheng Yu , Meiying Zhang , Bin Luo , Hongyang Jing , Yue Yu , Shunqi Wang , Shiwen Luo

Epilepsy is characterized by the typical symptom of seizure, and anti-seizure medications are the main therapeutic method in clinical, but the effects of these therapy have not been satisfactory. To find a better treatment, it makes sense to further explore the regulatory mechanisms of seizures at genetic level. Lrp4 regionally expresses in mice hippocampus where is key to limbic epileptogenesis. It is well known that neurons release a high level of glutamate during seizures, and it has been reported that Lrp4 in astrocytes down-regulates glutamate released from neurons. However, it is still unclear whether there is a relationship between Lrp4 expression level and seizures, and whether Lrp4 plays a role in seizures. We found that seizures induced by pilocarpine decreased Lrp4 expression level and increased miR-351-5p expression level in mice hippocampus. Glutamate reduced Lrp4 expression and enhanced miR-351-5p expression in cultured hippocampal astrocytes, and these effects can be partially attenuated by AP5. Furthermore, miR-351-5p inhibitor lessened the reduction of Lrp4 expression in glutamate treated hippocampal astrocytes. Local reduction of Lrp4 in hippocampus by sh Lrp4 lentivirus injection in hippocampus increased the threshold of seizures in pilocarpine or pentylenetetrazol (PTZ) injected mice. These results indicated that high released glutamate induced by seizures down-regulated astrocytic Lrp4 through increasing miR-351-5p in hippocampal astrocytes via activating astrocytic NMDA receptor, and locally reduction of Lrp4 in hippocampus increased the threshold of seizures. Lrp4 in hippocampal astrocytes appears to serve as a negative feedback factor in seizures. This provides a new potential therapeutic target for seizures regulation.

中文翻译:

海马星形胶质细胞中的Lrp4是癫痫发作的负反馈因子

癫痫病以癫痫发作的典型症状为特征,抗癫痫药是临床上的主要治疗方法,但这些治疗方法的效果并不令人满意。为了找到更好的治疗方法,在基因水平上进一步探索癫痫发作的调节机制是有意义的。Lrp4在小鼠海马区域表达,这是边缘性癫痫发生的关键。众所周知,在癫痫发作期间神经元释放出高水平的谷氨酸,并且据报道,星形胶质细胞中的Lrp4下调了从神经元释放的谷氨酸。然而,仍不清楚Lrp4表达水平与癫痫发作之间是否存在关系,以及Lrp4是否在癫痫发作中起作用。我们发现毛果芸香碱诱发的癫痫发作降低了小鼠海马中Lrp4表达水平并增加了miR-351-5p表达水平。谷氨酸降低了培养的海马星形胶质细胞中Lrp4的表达并增强了miR-351-5p的表达,这些作用可以被AP5部分减弱。此外,miR-351-5p抑制剂减少了谷氨酸处理的海马星形胶质细胞中Lrp4表达的减少。在海马体中注射sh Lrp4慢病毒后,海马中Lrp4的局部降低增加了毛果芸香碱或戊四氮(PTZ)注射小鼠的癫痫发作阈值。这些结果表明,癫痫发作诱发的高释放谷氨酸盐通过激活星形胶质细胞NMDA受体,通过增加海马星形胶质细胞中miR-351-5p的表达而下调星形胶质细胞Lrp4,而海马中Lrp4的局部降低会增加癫痫发作的阈值。海马星形胶质细胞中的Lrp4似乎是癫痫发作的负反馈因子。这为癫痫发作调节提供了新的潜在治疗靶标。
更新日期:2020-11-23
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