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

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

Author information

1
Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig Maximilian University of Munich, Munich, Germany michael.wehr@med.uni-muenchen.de moritz.rossner@med.uni-muenchen.de.
2
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
3
Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig Maximilian University of Munich, Munich, Germany.
4
Cellular Neurophysiology, Center of Physiology, Hannover Medical School, Hannover, Germany.
5
Systasy Bioscience GmbH, Munich, Germany.
6
Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Munich, Germany.
7
Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Münster, Münster, Germany.
8
Center for Systems Neuroscience (ZSN), Hanover, Germany.

Abstract

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

PMID:
28743784
PMCID:
PMC5653977
DOI:
10.15252/emmm.201707691
[Indexed for MEDLINE]
Free PMC Article

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