ABSTRACT
60This chapter describes the role of microRNA dysregulation in the development of schizophrenia (SCZ) with particular reference to functional changes arising from this dysregulation. The chapter begins with evidence from both postmortem and peripheral blood studies that microRNAs are indeed dysregulated in SCZ. This dysregulation is believed to arise in part from genetic mutations in the microRNA transcript; therefore, a thorough review of the studies that identify microRNA single-nucleotide polymorphisms (SNPs) in SCZ population is subsequently provided. Particular emphasis is placed on the mechanism by which these microRNA SNPs may give rise to functional microRNA and downstream gene expression changes. In addition to these local SNPs, a second subset of studies indicates that microRNA dysregulation in SCZ may arise in part from global mutations in the microRNA biogenesis pathway. These studies are discussed with particular reference to the links that have been discovered between dysregulation of genes involved in the microRNA biogenesis pathway and copy number variations that are established candidate risk factors for SCZ, such as the 22q11.2 microdeletion. This evidence is then followed by an interrogation of the pharmacological studies, some of which have shown that antipsychotic medication used in the treatment of SCZ has a measurable effect on microRNA expression. Finally, as the information related above is highly heterogeneous, an attempt is made to collate the evidence around the mechanisms through which these diverse microRNA candidate SNPs affect mRNA expression and how this in turn has downstream effects on the expression of genes and proteins that have already been associated with SCZ. To this end, there is a detailed examination of studies that have examined the functional implications of microRNA dysregulation on SCZ-related targets. Evidence is presented from groups that have employed pathway analysis to determine the downstream effects of microRNA dysregulation, which have consistently implicated pathways involved in nervous system development and functioning. In conclusion, this chapter provides a thorough review of the body of evidence surrounding microRNA dysregulation in SCZ with the aim of determining the functional significance of this dysregulation. This investigation may indicate potential convergence pathways for a genetically heterogeneous disorder while simultaneously shedding light on the method by which differential microRNA expression produces dysregulation in these pathways.
