Neuregulin 1-erbB signaling in schizophrenia

描述(申请人提供)：最近的分子遗传学研究表明，神经调节蛋白1(NRG1)及其受体erbB与精神分裂症的病理生理学有关。在NRG1受体中，ERBB4因其在神经发育和N-甲基-D-天冬氨酸(NMDA)受体信号调节中的重要作用而备受关注。我们最近研究了NRG1-ERBB4机制在精神分裂症和对照组死后脑中的表达和转导。使用一种新的死后组织刺激方法，我们发现精神分裂症受试者前皮质中NRG1-ERBB4信号发生了显著变化。首先，NRG1诱导的ERBB4活化(通过ERBB4的酪氨酸磷酸化及其与PSD-95的关联来衡量)显著增强，而NRG1或ERBB4的表达水平没有改变。其次，精神分裂症患者ERBB4与PSD-95和NMDAR的关联性以及PSD-95‘S与NMDAR的偶联也发生了显著改变。第三，刺激NRG1减弱了人类前额叶皮质中NMDAR的激活，如在啮齿动物中所示。NMDAR的激活，通过受体的酪氨酸磷酸化来衡量，在精神分裂症患者中显著减弱，我们认为这是患者大脑中NMDAR功能低下的第一个直接证据。最后，当NMDA和NRG1共同刺激脑组织时，精神分裂症患者NRG1引起的NMDA衰减更大，这表明精神分裂症中NRG1-ERBB4信号的异常调节可能与NMDAR功能低下有关。我们的中心假设是，精神分裂症中ERBB4信号的改变与PSD中蛋白质-蛋白质相互作用的改变有关，包括NMDAR复合体。这项提议的目的是测试一个模型，在该模型中，精神分裂症中ERBB4-突触后密度(PSD)蛋白关联改变导致ERBB4信号增强，进而导致NMDAR功能低下。通过这样做，我们将能够探索PSD中调节异常的蛋白质-蛋白质相互作用是否是精神分裂症的病理生理机制。目标1将首先评估过度活跃的ERBB4信号在精神分裂症中是否具有脑区或配体特异性。AIM 2将专门研究ERBB4和其他PSD蛋白之间的蛋白质相互作用。目的3，进一步研究ERBB4基因异常对NMDAR信号转导的影响，并探讨可能的机制。

DESCRIPTION (provided by applicant): Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor, erbB, in the pathophysiology of schizophrenia. Among NRG 1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in modulation of N-methyl-D-aspartate (NMDA) receptor signaling. We have recently examined the expression and transduction of the NRG1- erbB4 mechanism in the postmortem brains of schizophrenia and control subjects. Using a novel postmortem tissue stimulation approach, we found striking alterations of NRG1- erbB4 signaling in the prefrental cortex of schizophrenia subjects. First, NRG1-induced erbB4 activation, measured by tyrosine phosphorylation of erbB4 and its association with PSD-95, was dramatically enhanced, while the expression levels of NRG1 or erbB4 were not altered. Second, the association of erbB4 with PSD-95 and NMDAR as well as PSD-95's coupling with NMDAR were also significantly altered in schizophrenia. Third, NRG1 stimulation attenuates NMDAR activation in the human prefrontal cortex as shown in rodents. NMDAR activation, measured by tyrosine phosphorylation of the receptors, was significantly attenuated in schizophrenia subjects, which we believe to be the first direct demonstration of NMDAR hypofunction in the brains of patients. Finally, when the brain tissues were co-stimulated with NMDA and NRG1, NRG1 induced NMDA attenuation was even greater in schizophrenia subjects, suggesting that the dyregulated NRG1 -erbB4 signaling in schizophrenia may contribute to NMDAR hypofunction. Our central hypothesis is that altered erbB4 signaling in schizophrenia is associated with altered protein -protein interactions in the PSD, including NMDAR complexes. The aims of this proposal are designed to test a model in which altered erbB4 - postsynaptic density (PSD) protein association in schizophrenia leads to enhanced erbB4 signaling, which in turn results in NMDAR hypofunction. By doing so, we will be able to explore whether dysregulated protein - protein interactions in the PSD is a pathophysiologic mechanism for schizophrenia. Aim 1 will first assess whether hyperactive erbB4 signaling is brain region- or ligand-specific in schizophrenia. Aim 2 will specifically address protein protein interactions among erbB4 and other PSD proteins. Aim 3, will further characterize the impact of erbB4 dysregulation on NMDAR signaling and explore possible mechanisms.