| 1 | Proc. Natl. Acad. Sci. U.S.A. 2012 Jul 109: 12165-70 |
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| PMID | 22689948 |
| 标题 | 精神分裂症和磷酸肌醇3-激酶-P110中的神经调节蛋白1-ERBB4-PI3K信号传导？抑制是一种潜在的治疗策略。 |
| 抽象的 | Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated inschizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated withschizophreniaand 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 byschizophrenia-associated ErbB4 genotype andPIK3CD水平和患者患者的水平受损schizophrenia。在人脑中，相同的ERBB4基因型再次预测增加PIK3CDexpression. Pharmacological inhibition of p110? using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reversesschizophrenia-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显示与schizophrenia。我们的数据提供了洞察Erb的机制B4 association withschizophrenia; 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关键字 | schizophrenia |
| 2 | J. Neurosci. 2016 Apr 36: 4859-75 |
| PMID | 27122041 |
| 标题 | Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model. |
| 抽象的 | schizophreniais 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 withschizophrenia。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 withschizophreniaand 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 toschizophrenia, 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 forschizophrenia风险;证明缺陷在成年期在药理学上是可逆的；并进一步突出显示P110？作为抗精神病药的靶标。 schizophreniais a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk forschizophreniahave 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 withschizophreniain 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 ofschizophrenia。 |
| SCZ关键字 | schizophrenia |
| 3 | Pharmacology 2016 -1 98: 4-12 |
| PMID | 26960157 |
| 标题 | Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway. |
| 抽象的 | ThePIK3CD基因编码磷酸肌醇3-激酶（PI3K）的三角洲催化亚基，这是神经蛋白1- downstream erbb4-pi3k信号通路的元素，最近被确定为用于处理治疗的分子靶标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. U-87MG人胶质母细胞瘤细胞系用作实验模型。定量聚合酶链反应用于检查mRNA和酶联免疫吸附测定的表达以进行蛋白质表达。 在大脑中的临床环境中达到浓度，CLO以及OLA和QUE的程度较小，但不是AMI，但可能不降低了halo，降低了的mRNA表达PIK3CD。该基因的蛋白质表达未证实mRNA表达谱。 The tested antipsychotic drugs (APDs) in the U-87MG glioblastoma cell line differentially regulates the mRNA expression ofPIK3CD; 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关键字 | schizophrenia |