MicroRNA-137 regulates a glucocorticoid receptor-dependent signalling network: Implications for the etiology of schizophrenia

Background: schizophrenia is a highly heritable neurodevelopmental disorder. a genetic variant of microrna-137 (mir-137) has yielded significant genome-wide association with schizophrenia,suggesting that this mirna plays a key role in its etiology. therefore,a molecular network of interacting mir-137 targets may provide insights into the biological processes underlying schizophrenia. methods:we first used bioinformatics tools to obtain and analyze predicted human and mouse mir-137 targets. we then determined mir-137 levels in rat barrel cortex after environmental enrichment (ee),a neuronal plasticity model that induces upregulation of several predicted mir-137 targets. subsequently,expression changes of these predicted targets were examined through loss of mir-137 function experiments in rat cortical neurons. finally,we conducted bioinformatics and literature analyses to examine the targets that were upregulated upon mir-137 downregulation. results:predicted human and mouse mir-137 targets were enriched in neuronal processes,such as axon guidance,neuritogenesis and neurotransmission. the mir-137 levels were significantly downregulated after ee,and we identified 5 novel mir-137 targets through loss of mir-137 function experiments. these targets fit into a glucocorticoid receptor-dependent signalling network that also includes 3 known mir-137 targets with genome-wide significant association with schizophrenia. limitations:the bioinformatics analyses involved predicted human and mouse mir-137 targets owing to lack of information on predicted rat mir-137 targets,whereas follow-up experiments were performed with rats. furthermore,indirect effects in the loss of mir-137 function experiments cannot be excluded. conclusion:we have identified a mir-137-regulated protein network that contributes to our understanding of the molecular basis of schizophrenia and provides clues for future research into psychopharmacological treatments for schizophrenia. © 2014 canadian medical association.