| 1 | Proc. Natl. Acad. Sci. U.S.A. 2012 Jul 109: 12165-70 |
|---|---|
| PMID | 22689948 |
| Title | Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110? inhibition as a potential therapeutic strategy. |
| 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, p110? (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? 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?, and AKT; and suggest that p110? is a previously undescribed therapeutic target for the treatment of psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 2 | J. Neurosci. 2016 Apr 36: 4859-75 |
| PMID | 27122041 |
| Title | Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model. |
| Abstract | schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110?, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110? reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110? as a target for antipsychotic drug development. schizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory-inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 3 | Pharmacology 2016 -1 98: 4-12 |
| PMID | 26960157 |
| Title | Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway. |
| Abstract | The PIK3CD gene encodes the delta catalytic subunit of phosphoinositide 3-kinase (PI3K), an element of the neuregulin 1-downstream ErbB4-PI3K signaling pathway, which was recently identified as a molecular target for the treatment of schizophrenia. The aim of the study was to examine the effect of haloperidol (HALO), clozapine (CLO), olanzapine (OLA), quetiapine (QUE) and amisulpride (AMI) on the mRNA and protein expression of genes encoding the elements of ErbB4-PI3K pathway, in a human central nervous system cell line. The U-87MG human glioblastoma cell line was used as an experimental model. Quantitative polymerase chain reaction was used to examine the expression of mRNA and enzyme-linked immunosorbent assay for protein expression. At concentrations reached in clinical settings in the brain, CLO, as well as OLA and QUE to a lesser extent, but not AMI and probably not HALO, decreased the mRNA expression of PIK3CD. Protein expression of the gene did not confirm the mRNA expression profile. The tested antipsychotic drugs (APDs) in the U-87MG glioblastoma cell line differentially regulates the mRNA expression of PIK3CD; however, the protein expression does not confirm these findings. The results of the study may help deepen the understanding of the mechanism of action of APDs. |
| SCZ Keywords | schizophrenia |