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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 publication

DOI

10.1073/pnas.1206118109

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

24/07/2012

Volume

109

Pages

12165 - 12170

Keywords

Adenine, Amphetamine, Analysis of Variance, Animals, Antipsychotic Agents, B-Lymphocytes, Blotting, Western, Cell Line, Transformed, Class I Phosphatidylinositol 3-Kinases, Flow Cytometry, Genetic Association Studies, Humans, Mice, Molecular Structure, Neuregulin-1, Phosphatidylinositol 3-Kinases, Phosphorylation, Quinazolines, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Receptor, Epidermal Growth Factor, Receptor, ErbB-4, Reverse Transcriptase Polymerase Chain Reaction, Schizophrenia, Signal Transduction