1. Gene expression in the brain is dynamically regulated across the lifespan. The temporal dynamics of gene expression is conferred by transcriptional and posttranscriptional regulation. microRNAs (miRNAs) play important roles in the posttranscriptional regulation of gene expression during brain development. miRNAs are small (16-25 nt) non-coding RNAs that bind to the 3 UTR of their target mRNAs through imperfect complementarity to destabilize mRNAs or inhibit translation. miRNA expression in the brain is developmentally regulated and correlates with cortical maturation. However, the temporal dynamics of miRNA expression in human brains has not been delineated and it remains largely unclear whether miRNAs regulate the temporal dynamics of mRNAs. In this study, we delineated the temporal dynamics of miRNAs expressed in the human DLPFC across the majority of the lifespan. Our analyses show that in normal brains, miRNAs and mRNAs have different temporal dynamics and that most miRNAs are preferentially expressed in one specific developmental period. In the DLPFC of schizophrenia patients, miRNAs exhibiting expression changes are over-represented by those preferentially expressed in infancy, and miRNAs normally enriched in infancy or adulthood change in directions opposite to their normal developmental trajectories. 2. 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. Here, 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 synaptic genes, which are known to be dysregulated in schizophrenia patients. Hence, miRNAs may contribute to the synaptopathology of schizophrenia. This possibility is further supported by our finding that most miRNAs altered in schizophrenia cases are expressed predominantly in one specific developmental period in unaffected people when synaptic connections are formed and refined. Moreover, the targets of miRNAs altered in schizophrenia are enriched for genes with de novo single nucleotide variants (SNVs) associated with schizophrenia. These findings reveal a tight temporal control of miRNA expression in human DLPFC, suggest connections among dysregulated miRNA expression, disturbed brain development and synaptic function in schizophrenia, and identify infancy as a potential critical period in the development of schizophrenia.
