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

A. Valles, GJ. Martens, P. de Weerd, G. Poelmans, A. Aschrafi

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number130269
Pages (from-to)312-320
Number of pages9
JournalJournal of Psychiatry & Neuroscience
Volume39
Issue number5
DOIs
Publication statusPublished - Sep 2014

Keywords

  • DORSOLATERAL PREFRONTAL CORTEX
  • AUTISM SPECTRUM DISORDERS
  • ALZHEIMERS-DISEASE
  • MOUSE MODEL
  • ENVIRONMENTAL ENRICHMENT
  • SYNAPTIC PLASTICITY
  • INTELLECTUAL DISABILITY
  • TARGET PREDICTION
  • AMYLOID-BETA
  • MIR-137

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