title: MicroRNA-137 regulates a glucocorticoid receptor-dependent signalling network: implications for the etiology of schizophrenia.
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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurocognition, Faculty of Psychology and Neurosciences, Maastricht University, Maastricht, the Netherlands; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen, Nijmegen, the Netherlands.
authors.forename: Astrid
authors.initials: A
authors.lastname: Vallès
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen, Nijmegen, the Netherlands.
authors.forename: Gerard J M
authors.initials: GJ
authors.lastname: Martens
authors.affiliation: Department of Neurocognition, Faculty of Psychology and Neurosciences, Maastricht University, Maastricht, the Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: De Weerd
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen, Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: Poelmans
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, the Netherlands.
authors.forename: Armaz
authors.initials: A
authors.lastname: Aschrafi
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology; D004777:Environment; D006799:Housing, Animal; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C545567:MIRN137 microRNA, human; C551799:MIRN137 microRNA, mouse; C000595679:MIRN137 microRNA, rat; D035683:MicroRNAs; D011965:Receptors, Glucocorticoid