Schizophrenia as a Disorder of Glutamate Receptor Trafficking

描述（由申请人提供）：这是一个竞争性的继续拨款线集中在精神分裂症死后大脑受体为基础的异常的申请。虽然我们和其他人已经发表了精神分裂症患者大脑中谷氨酸受体表达异常的发现，但许多发现都很微妙，而且往往相互矛盾。这些关于NMDA和AMPA受体表达的相互矛盾的研究使我们在本基金和项目的最后阶段重新考虑“精神分裂症的谷氨酸假说”，而不是“太多”或“太少”的受体，而是管理总受体库的细胞生物学过程的改变。我们假设精神分裂症患者存在离子型谷氨酸受体运输、传递、树突定位、回收和降解的异常。我们的首要假设是，精神分裂症患者大脑中的NMDA和AMPAR发生了变化，涉及特定细胞内过程的异常。我们在过去5年中从精神分裂症患者死后额叶皮质样本中生成的数据支持了这一模型，有证据表明AMPA和NMDAR复合物加速退出内质网（ER）和高尔基体，包括N-连接糖基化的变化和ER退出和保留信号的表达，这些受体的异常前向运输，以及树突棘AMPA受体内体含量的变化。总之，这些异常与NMDA和/或AMPAR功能降低一致，即使这些受体的总细胞水平似乎是正常的。我们假设，根据我们以前的工作，在这些大脑中的一个根本缺陷是异常处理的离子型受体复合物在突触后密度的突触，和前向贩运的证据是稳态驱动的细胞内克服这一缺陷。在本申请中，我们提出，使用来自精神分裂症患者和对照组的死后脑样品，以确定我们的发现对NMDA和AMPAR以及额叶皮质的特异性;确定与多巴胺能神经传递相关的关键蛋白的N-连接和O-连接糖基化的异常程度;检查与运输和突触靶向相关的细胞内蛋白质和翻译后修饰;并直接检查这些受体在突触后密度和其他突触周围区室中的表达。这些数据将使我们能够测试我们的精神分裂症与树突棘谷氨酸受体动力学异常相关的模型。

DESCRIPTION (provided by applicant): This is an application for a competing continuation of a grant line focused on receptor-based abnormalities in postmortem brain in schizophrenia. While we and others have published findings of abnormal glutamate receptor expression in the brain in schizophrenia, many findings have been subtle and often contradictory. These conflicting studies on the expression of NMDA and AMPA receptors led us in the last period of this grant and project to reconsider the "glutamate hypothesis of schizophrenia" not as "too many" or "too few" receptors, but rather one of alterations in the cell biological processes that manage the total pool of receptors. We hypothesized that there are abnormalities of ionotropic glutamate receptor trafficking, delivery, dendritic localization, recycling, and degradation in schizophrenia. Our overarching hypothesis was that there are changes in NMDA and AMPARs in the brain in schizophrenia that involve abnormalities of specific intracellular processes. The data we have generated from postmortem frontal cortex samples in schizophrenia over the past 5 years support this model, with evidence for accelerated exit from the endoplasmic reticulum (ER) and Golgi apparatus of AMPA and NMDAR complexes including changes in N-linked glycosylation and expression of ER exit and retention signals, abnormal forward trafficking of these receptors, and changes in endosomal content of the AMPA receptors at the dendritic spine. Taken together, these abnormalities are consistent with diminished NMDA and/or AMPAR function even though total cellular levels of these receptors appears to be normal. We hypothesize, based on our prior work, that a fundamental defect in these brains is abnormal handling of the ionotropic receptor complex at the postsynaptic density in the synapse, and the evidence for forward trafficking is homeostatically driven within the cell to overcome this deficiency. We propose in this application, using postmortem brain samples from persons with schizophrenia and a comparison group, to determine the specificity of our findings to the NMDA and AMPARs as well as to the frontal cortex; to determine the extent of abnormality of N-linked and O-linked glycosylation of key proteins associated with glutamatergic neurotransmission; to examine intracellular proteins and posttranslational modifications associated with trafficking and synaptic targeting; and directly examine expression of these receptors in the postsynaptic density and other perisynaptic compartments. These data will permit us to test our model of schizophrenia being associated with abnormality of glutamate receptor dynamics in the dendritic spine.