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（NRG 1）及其受体erbB与精神分裂症的病理生理有关。在NRG 1受体中，erbB 4由于其在神经发育和调节N-甲基-D-天冬氨酸（NMDA）受体信号传导中的关键作用而特别令人感兴趣。我们最近研究了NRG 1-erbB 4机制在精神分裂症和对照组死后大脑中的表达和转导。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的前额叶皮层中NRG 1-erbB 4信号发生了显着的变化。首先，NRG 1诱导的erbB 4活化，通过erbB 4的酪氨酸磷酸化及其与PSD-95的相关性来测量，显著增强，而NRG 1或erbB 4的表达水平没有改变。第二，erbB 4与PSD-95和NMDAR的关联以及PSD-95与NMDAR的偶联在精神分裂症中也显著改变。第三，NRG 1刺激减弱人前额叶皮层中的NMDAR激活，如啮齿动物中所示。通过受体的酪氨酸磷酸化测量的NMDAR激活在精神分裂症受试者中显著减弱，我们认为这是患者大脑中NMDAR功能减退的第一个直接证明。最后，当脑组织与NMDA和NRG 1共刺激时，NRG 1诱导的NMDA衰减在精神分裂症受试者中甚至更大，这表明精神分裂症中NRG 1-erbB 4信号转导失调可能导致NMDAR功能低下。我们的中心假设是，精神分裂症中erbB 4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复合物。该建议的目的是测试一个模型，其中改变erbB 4-突触后密度（PSD）蛋白关联精神分裂症导致增强erbB 4信号，这反过来又导致NMDAR功能减退。通过这样做，我们将能够探索PSD中失调的蛋白质-蛋白质相互作用是否是精神分裂症的病理生理机制。目的1将首先评估过度活跃的erbB 4信号传导在精神分裂症中是否是脑区域或配体特异性的。目的2将专门解决erbB 4和其他PSD蛋白之间的蛋白质相互作用。目的3，进一步研究erbB 4异常对NMDAR信号转导的影响，并探讨其可能的机制。

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.