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Nonetheless, pathway\u2010directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell\u2010based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1\u2010ERBB4 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\u2010relevant 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\u2010mediated mode\u2010of\u2010action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.<\/jats:p>","DOI":"10.15252\/emmm.201707691","type":"journal-article","created":{"date-parts":[[2017,7,25]],"date-time":"2017-07-25T20:10:15Z","timestamp":1501013415000},"page":"1448-1462","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Spironolactone is an antagonist of NRG1\u2010ERBB4 signaling and schizophrenia\u2010relevant endophenotypes in mice"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1770-8323","authenticated-orcid":false,"given":"Michael C","family":"Wehr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilko","family":"Hinrichs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena M","family":"Brz\u00f3zka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilmann","family":"Unterbarnscheidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Herholt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan P","family":"Wintgens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergi","family":"Papiol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Clara","family":"Soto\u2010Bernardini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mykola","family":"Kravchenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus\u2010Armin","family":"Nave","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven P","family":"Wichert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Falkai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus H","family":"Schwab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0667-3420","authenticated-orcid":false,"given":"Moritz J","family":"Rossner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,25]]},"reference":[{"key":"BFEMMM201707691_CR1","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.celrep.2014.07.026","volume":"8","author":"A Agarwal","year":"2014","unstructured":"Agarwal A, Zhang M, Trembak\u2010Duff I, Unterbarnscheidt T, Radyushkin K, Dibaj P, Martins de Souza D, Boretius S, Brz\u00f3zka MM, Steffens H et\u00a0al (2014) Dysregulated expression of neuregulin\u20101 by cortical pyramidal neurons disrupts synaptic plasticity. 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