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.
