Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy.
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.
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. lawa@mail.nih.gov
Amanda J
AJ
Law
Yanhong
Y
Wang
Yoshitatsu
Y
Sei
Patricio
P
O'Donnell
Patrick
P
Piantadosi
Francesco
F
Papaleo
Richard E
RE
Straub
Wenwei
W
Huang
Craig J
CJ
Thomas
Radhakrishna
R
Vakkalanka
Aaron D
AD
Besterman
Barbara K
BK
Lipska
Thomas M
TM
Hyde
Paul J
PJ
Harrison
Joel E
JE
Kleinman
Daniel R
DR
Weinberger
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000661:Amphetamine / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001402:B-Lymphocytes; D015153:Blotting, Western; D002461:Cell Line, Transformed; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D056726:Genetic Association Studies; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D020890:Neuregulin-1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D066247:Receptor, ErbB-4; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000225:Adenine; D000661:Amphetamine; D014150:Antipsychotic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D066247:Receptor, ErbB-4; C477872:IC 87114; C094131:NRG1 protein, human; C486018:PIK3CD protein, human; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat