Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12165-70. doi: 10.1073/pnas.1206118109. Epub 2012 Jun 11.
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.
神经调节蛋白 1（NRG1）和 ErbB4 是关键的神经发育基因，与精神分裂症有关，但介导机制尚不清楚。在这里，我们确定了一个与精神分裂症相关的遗传调控、药物可靶向的风险途径，与 ErbB4 遗传变异有关，涉及到一种与 PI3K 相关的 ErbB4 受体（CYT-1）和磷酸肌醇 3-激酶亚基 p110δ（PIK3CD）表达增加。在人类淋巴母细胞中，NRG1 介导的磷酯酰肌醇，3,4,5 三磷酸[PI（3,4,5）P3]信号受与精神分裂症相关的 ErbB4 基因型和 PIK3CD 水平的预测，并且在精神分裂症患者中受损。在人类大脑中，同样的 ErbB4 基因型再次预测 PIK3CD 表达增加。使用小分子抑制剂 IC87114 抑制 p110δ 的药理学抑制作用可阻断安非他命在精神分裂症的小鼠药理学模型中的作用，并可逆转大鼠新生海马损伤模型中的精神分裂症相关表型。与这些抗精神病特性一致，IC87114 增加了治疗小鼠大脑中的 AKT 磷酸化，暗示了一种作用机制。最后，在两项基于家族的遗传研究中，PIK3CD 显示与精神分裂症有关的证据。我们的数据提供了对 ErbB4 与精神分裂症关联机制的深入了解；揭示了 NRG1-ErbB4、p110δ 和 AKT 之间以前未被识别的生物学和疾病联系；并表明 p110δ 是治疗精神疾病的以前未被描述的治疗靶点。
