Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Amanda J. Law, Yanhong Wang, Yoshitatsu Sei, Patricio O'Donnell, Patrick Piantadosi, Francesco Papaleo, Richard E. Straub, Wenwei Huang, Craig J. Thomas, Radhakrishna Vakkalanka, Aaron D. Besterman, Barbara K. Lipska, Thomas M. Hyde, Paul J. Harrison, Joel E. Kleinman, Daniel R. Weinberger

Research output: Contribution to journalArticle

Abstract

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, p110δ (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 p110δ 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, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.

Original languageEnglish (US)
Pages (from-to)12165-12170
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number30
DOIs
StatePublished - Jul 24 2012

Keywords

  • AKT
  • Development
  • Neuregulin 3
  • Neuroleptic

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy'. Together they form a unique fingerprint.

  • Cite this

    Law, A. J., Wang, Y., Sei, Y., O'Donnell, P., Piantadosi, P., Papaleo, F., Straub, R. E., Huang, W., Thomas, C. J., Vakkalanka, R., Besterman, A. D., Lipska, B. K., Hyde, T. M., Harrison, P. J., Kleinman, J. E., & Weinberger, D. R. (2012). Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy. Proceedings of the National Academy of Sciences of the United States of America, 109(30), 12165-12170. https://doi.org/10.1073/pnas.1206118109