Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice

EMBO Mol Med. 2017 Oct;9(10):1448-1462. doi: 10.15252/emmm.201707691.


Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia-relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4-mediated mode-of-action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.

Keywords: NRG1‐ERBB4; drug repositioning; schizophrenia; spironolactone; split TEV assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior Rating Scale
  • Cell Line, Tumor
  • Coculture Techniques
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mineralocorticoid Receptor Antagonists / pharmacology*
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Neuregulin-1 / antagonists & inhibitors*
  • Phosphorylation / drug effects
  • Receptor, ErbB-4 / antagonists & inhibitors*
  • Schizophrenia / drug therapy*
  • Spironolactone / pharmacology*
  • Spironolactone / therapeutic use


  • Mineralocorticoid Receptor Antagonists
  • Neuregulin-1
  • Nrg1 protein, mouse
  • Spironolactone
  • Erbb4 protein, mouse
  • Receptor, ErbB-4