Neuregulin 1-erbB signaling in schizophrenia

描述（由申请人提供）：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）受体信号传导调节中的关键作用而受到特别关注。我们最近研究了NRG1- erbB4在精神分裂症和对照组死后大脑中的表达和转导机制。使用一种新颖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NRG1- erbB4信号的显著改变。首先，通过酪氨酸磷酸化erbB4及其与PSD-95的关联测量，NRG1诱导的erbB4激活显著增强，而NRG1或erbB4的表达水平没有改变。第二，erbB4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有显著改变。第三，在啮齿类动物中，NRG1刺激会减弱人类前额叶皮层NMDAR的激活。通过酪氨酸磷酸化受体测量的NMDAR激活在精神分裂症受试者中显着减弱，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NMDA和NRG1共同刺激脑组织时，精神分裂症患者NRG1诱导的NMDA衰减更大，提示精神分裂症患者NRG1 -erbB4信号失调可能导致NMDAR功能减退。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-蛋白相互作用的改变有关，包括NMDAR复合物。本研究的目的是测试一种模型，在这种模型中，精神分裂症患者erbB4 -突触后密度（PSD）蛋白关联的改变会导致erbB4信号传导增强，进而导致NMDAR功能减退。通过这样做，我们将能够探索PSD中蛋白-蛋白相互作用失调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erbB4信号在精神分裂症中是脑区特异性还是配体特异性。Aim 2将专门讨论erbB4和其他PSD蛋白之间的蛋白相互作用。目的3，将进一步表征erbB4失调对NMDAR信号的影响，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.