The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.

中文翻译：

---

调节了谷氨酸受体表达的改变了精神病的miRNA的外泌体分泌受到抗精神病药的影响。

小分泌微囊泡（称为外泌体）通过其microRNA（miRNA）货物影响神经元和神经胶质功能的能力已将其定位为一种新颖有效的细胞间通讯方法。但是，关于外泌体分泌的miRNA在调节谷氨酸受体基因表达中的作用及其与精神分裂症（SCZ）和躁郁症（BD）的相关性知之甚少。在SCZ（N = 29; 20男性和9女性），BD（N = 26; 12男性和14女性）的眶额皮质（OFC）中使用成熟的miRNA分析和定量实时PCR（qRT-PCR）在未受影响的对照组（N = 25； 21名男性和4名女性）受试者中，我们发现了miR-223，这是一种分泌外泌体的miRNA，靶向谷氨酸受体，在死亡时患有精神病的精神病史阳性的SCZ和BD患者的OFC中，miRNA的水平升高，并且与靶标谷氨酸离子受体NMDA型亚基2B（GRIN2B）和谷氨酸的表达缺失呈负相关离子受体AMPA型亚基2（GRIA2）。此外，OFC中miR-223水平的变化分别与炎症和GABA能基因的表达呈正相关和负相关。此外，发现miR-223富含星形胶质细胞并通过外泌体分泌，抗精神病药被证明以细胞特异性方式控制其细胞和外泌体定位。此外，在神经元培养物中添加星形细胞外泌体会导致miR-223表达显着增加，并显着降低Grin2b和Gria2 mRNA的水平，这与miR-223的表达强烈反相关。最后，星形胶质细胞miR-223的抑制作用消除了外泌体介导的神经元Grin2b表达的减少。两者合计，我们的结果表明控制神经元基因表达的精神病改变和神经胶质细胞丰富的miRNA的外泌体分泌受抗精神病药的调节。