Impact of clozapine on the expression of miR-675-3p in plasma exosomes derived from patients with schizophrenia

Recently, the expression changes of microRNAs (miRNAs) in the serum exosomes (EXO) of schizophrenia (SCZ) have been reported. The aim of this study was to investigate the global expression changes of miRNA derived from the plasma EXO of patients with treatment-resistant schizophrenia (TRS) and the effects of clozapine on miRNA expression. Global miRNA expression changes in plasma EXO between TRS and controls were studied using microarray analysis. Then, miRNA expressions among TRS, non-TRS, and controls were confirmed with quantitative qPCR experiments. We also studied changes in EXO miRNA expression with in-vitro SH-SY5Y cells. A microarray for miRNA expression analysis (nine controls vs. nine patients with TRS) revealed 13 up- and 18 downregulated miRNAs that were relevant to neuronal and brain development based on gene ontology analysis. Of those, upregulated miR-675-3p expression was successfully validated in the same cohort by qPCR experiments. Conversely, miR-675-3p expression levels were significantly decreased in the non-TRS cohort (50 controls vs. 50 patients without TRS without clozapine treatment). We identified global miRNA changes in plasma EXO derived from patients with SCZ that were relevant to neuronal functions, among which, hsa-miR-675-3p expression was upregulated by clozapine treatment.

近期已有研究报道了精神分裂症（schizophrenia, SCZ）患者血清外泌体（exosomes, EXO）内微小RNA（microRNAs, miRNAs）的表达变化。本研究旨在探讨难治性精神分裂症（treatment-resistant schizophrenia, TRS）患者血浆外泌体来源的miRNA整体表达谱变化，以及氯氮平对miRNA表达的调控作用。本研究通过微阵列分析，对比了TRS患者与健康对照者血浆外泌体的miRNA整体表达差异。随后，采用定量聚合酶链式反应（qPCR）实验验证了TRS患者、非TRS患者与健康对照者之间的miRNA表达水平差异。此外，本研究还通过体外培养的SH-SY5Y细胞，探究了外泌体miRNA表达的变化情况。针对miRNA表达分析的微阵列实验（9名健康对照vs.9名TRS患者）结果显示，经基因本体论分析后，共有13种上调miRNA与18种下调miRNA与神经元及大脑发育相关。其中，上调表达的miR-675-3p在同一队列中通过qPCR实验得到了成功验证。与之相反，在非TRS队列（50名健康对照vs.50名未接受氯氮平治疗的非TRS患者）中，miR-675-3p的表达水平显著降低。本研究明确了精神分裂症患者血浆外泌体来源的miRNA整体表达变化与神经元功能密切相关，其中hsa-miR-675-3p的表达可被氯氮平治疗上调。