Characterizing the Function of miRNAs in Neural Development, Synaptic Plasticity and Schizophrenia.

MiRNAs被认为与精神分裂症有关。MiRNA生物发生机制中编码miRNA或组件的基因突变与精神分裂症的风险增加有关。假设精神分裂症患者miRNA的表达存在异常。利用基因芯片和定量聚合酶链式反应，几个小组检测了精神分裂症患者死后脑中miRNA的表达，并一致地检测到miRNA表达的变化。然而，在患者大脑中的发现并不一致。在这个项目中，我们利用下一代测序技术来识别在精神分裂症患者大脑中差异表达的miRNAs。我们还分析了精神药物和吸烟对miRNA表达的影响。利用生物信息学，我们发现精神分裂症患者差异表达的miRNAs的靶标富含编码突触蛋白的基因和与精神分裂症风险相关的基因。在本报告期间，我们选择了几个在精神分裂症患者中表现出最显著变化的miRNAs，并产生了在小鼠大脑中过度表达和击倒它们的试剂。我们将使用这些试剂来检测miRNA表达变化对小鼠突触生理和行为的影响。我们还建立了人诱导多能干细胞(IPSC)的培养，并将其分化为神经元。我们将使用这些细胞来检测miRNAs在IPSC来源的人类神经元发育中的功能。

miRNAs have been implicated in schizophrenia. Mutations in genes encoding miRNAs or components in the miRNA biogenesis machinery are associated with increased risk for schizophrenia. It is hypothesized that miRNA expression is aberrant in schizophrenia patients. Using microarray and quantitative PCR, several groups have examined miRNA expression in postmortem brains of schizophrenia patients, and consistently detected miRNA expression change. However, the findings in the patients brains have been inconsistent. In this project, we employed the next-generation sequencing technology to identify miRNAs that are differentially expressed in schizophrenic brains. We also analyzed the effect of psychiatric medications and tobacco smoking on miRNA expression. Using bioinformatics, we found that the targets of miRNAs differentially expressed in schizophrenia patients are enriched for genes encoding synaptic proteins and genes associated with risk for schizophrenia. During this reporting period, we selected a couple of miRNAs exhibiting the most significant changes in schizophrenia patients, and generated reagents to overexpress and knock down them in mouse brain. We will use these reagents to examine the effect of miRNA expression change on synaptic physiology and behavior in mice. We also established cultures of human induced pluripotent stem cells (IPSC) and differentiated them into neurons. We will use these cells to examine the function of miRNAs in the development of IPSC-derived human neurons.