TY - JOUR
T1 - Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy
AU - Law, Amanda J.
AU - Wang, Yanhong
AU - Sei, Yoshitatsu
AU - O'Donnell, Patricio
AU - Piantadosi, Patrick
AU - Papaleo, Francesco
AU - Straub, Richard E.
AU - Huang, Wenwei
AU - Thomas, Craig J.
AU - Vakkalanka, Radhakrishna
AU - Besterman, Aaron D.
AU - Lipska, Barbara K.
AU - Hyde, Thomas M.
AU - Harrison, Paul J.
AU - Kleinman, Joel E.
AU - Weinberger, Daniel R.
PY - 2012/7/24
Y1 - 2012/7/24
N2 - 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.
AB - 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.
KW - AKT
KW - Development
KW - Neuregulin 3
KW - Neuroleptic
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U2 - 10.1073/pnas.1206118109
DO - 10.1073/pnas.1206118109
M3 - Article
C2 - 22689948
AN - SCOPUS:84864340439
SN - 0027-8424
VL - 109
SP - 12165
EP - 12170
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -