Information exchange between neurons and astrocytes mediated by extracellular vesicles (EVs) is known to play a key role in the pathogenesis of central nervous system diseases. A key driver of epilepsy is the dysregulation of intersynaptic excitatory neurotransmitters mediated by astrocytes. Thus, we investigated the potential association between neuronal EV microRNAs (miRNAs) and astrocyte glutamate uptake ability in epilepsy. Here, we showed that astrocytes were able to engulf epileptogenic neuronal EVs, inducing a significant increase in the glutamate concentration in the extracellular fluid of astrocytes, which was linked to a decrease in glutamate transporter-1 (GLT-1) protein expression. Using sequencing and gene ontology (GO) functional analysis, miR-181c-5p was found to be the most significantly upregulated miRNA in epileptogenic neuronal EVs and was linked to glutamate metabolism. Moreover, we found that neuronal EV-derived miR-181c-5p interacted with protein kinase C-delta (PKCδ), downregulated PKCδ and GLT-1 protein expression and increased glutamate concentrations in astrocytes both in vitro and in vivo. Our findings demonstrated that epileptogenic neuronal EVs carrying miR-181c-5p decrease the glutamate uptake ability of astrocytes, thus promoting susceptibility to epilepsy.

中文翻译：

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携带miR-181c-5p的神经元小细胞外囊泡通过调节星形胶质细胞中的蛋白激酶C-δ/谷氨酸转运蛋白-1轴促进癫痫的发病机制

众所周知，细胞外囊泡（EV）介导的神经元和星形胶质细胞之间的信息交换在中枢神经系统疾病的发病机制中发挥着关键作用。癫痫的一个关键驱动因素是星形胶质细胞介导的突触间兴奋性神经递质的失调。因此，我们研究了癫痫中神经元 EV microRNA (miRNA) 与星形胶质细胞谷氨酸摄取能力之间的潜在关联。在这里，我们发现星形胶质细胞能够吞噬致癫痫神经元 EV，诱导星形胶质细胞细胞外液中谷氨酸浓度显着增加，这与谷氨酸转运蛋白 1 (GLT-1) 蛋白表达的减少有关。通过测序和基因本体 (GO) 功能分析，发现 miR-181c-5p 是致癫痫神经元 EV 中上调最显着的 miRNA，并且与谷氨酸代谢有关。此外，我们发现神经元 EV 衍生的 miR-181c-5p 与蛋白激酶 C-delta (PKCδ) 相互作用，下调 PKCδ 和 GLT-1 蛋白表达，并在体外和体内增加星形胶质细胞中的谷氨酸浓度。我们的研究结果表明，携带 miR-181c-5p 的致癫痫神经元 EV 会降低星形胶质细胞的谷氨酸摄取能力，从而促进癫痫的易感性。