{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:19:22Z","timestamp":1790785162416,"version":"4.1.0"},"reference-count":55,"publisher":"National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,7,24]]},"abstract":"<jats:p>Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110\u03b4 (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110\u03b4 using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110\u03b4, and AKT; and suggest that p110\u03b4 is a previously undescribed therapeutic target for the treatment of psychiatric disorders.<\/jats:p>","DOI":"10.1073\/pnas.1206118109","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T01:53:56Z","timestamp":1339466036000},"page":"12165-12170","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":134,"title":["Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110\u03b4 inhibition as a potential therapeutic strategy"],"prefix":"10.1073","volume":"109","author":[{"given":"Amanda J.","family":"Law","sequence":"first","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitatsu","family":"Sei","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Piantadosi","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Papaleo","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Straub","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"},{"name":"Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwei","family":"Huang","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Rockville, MD 20850;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J.","family":"Thomas","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Rockville, MD 20850;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radhakrishna","family":"Vakkalanka","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron D.","family":"Besterman","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"},{"name":"Howard Hughes Medical Institute\u2013National Institutes of Health Research Scholars Program, Howard Hughes Medical Institute, Chevy Chase, MD 20815; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara K.","family":"Lipska","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Hyde","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"},{"name":"Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Oxford, Oxford OX3 7JX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel E.","family":"Kleinman","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Weinberger","sequence":"additional","affiliation":[{"name":"Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"},{"name":"Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,6,11]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001558"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/342734"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2005.11.002"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.171"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.30275"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001878"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl449"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1155174"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08192"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08928"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.03.028"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/35000058"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702157104"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1815-08.2008"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2006.02.024"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1795"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2008.112"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602002103"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09915"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702953200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.42.26761"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(01)00065-2"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.12.8641"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800073200"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700373104"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1879"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2007.03.003"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-175-2_16"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20208"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.9.4330"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000869"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/stke.2001.65.pe1"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20387"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604032"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-07-3041"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.473"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2647"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)01480-3"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.03.035"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1380103"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.002642"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5074-06.2007"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.05.012"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0803522105"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1296"},{"key":"e_1_3_3_46_2","first-page":"2200","article-title":"Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans","volume":"118","author":"Tan HY","year":"2008","unstructured":"HY Tan, et al., Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest 118, 2200\u20132208 (2008).","journal-title":"J Clin Invest"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(00)00137-8"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.19.8906"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02246439"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/bcr1394"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2008.07.006"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708333105"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001994"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100012"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1418"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1206118109","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T20:46:32Z","timestamp":1649796392000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1206118109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,6,11]]},"references-count":55,"journal-issue":{"issue":"30","published-print":{"date-parts":[[2012,7,24]]}},"alternative-id":["10.1073\/pnas.1206118109"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1206118109","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,6,11]]},"assertion":[{"value":"2012-06-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}