Schizophrenia as a Disorder of Glutamate Receptor Trafficking

描述(由申请人提供)：这是一项竞争延续的拨款申请，重点是精神分裂症患者死后大脑中基于受体的异常。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异常表达的发现，但许多发现是微妙的，往往是相互矛盾的。这些关于NMDA和AMPA受体表达的相互矛盾的研究使我们在这项拨款和项目的最后阶段重新考虑了“精神分裂症的谷氨酸假说”，而不是“太多”或“太少”的受体，而是管理总受体池的细胞生物学过程的变化之一。我们假设精神分裂症患者存在离子亲性谷氨酸受体运输、递送、树突状细胞定位、循环和降解的异常。我们的主要假设是，精神分裂症患者大脑中存在NMDA和AMPAR的变化，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的死后额叶皮质样本中产生的数据支持这一模型，有证据表明AMPA和NMDAR复合体加速退出内质网(ER)和高尔基体，包括N-连接糖基化的变化以及ER退出和保留信号的表达，这些受体的异常正向运输，以及树突棘AMPA受体内体含量的变化。综上所述，这些异常与NMDA和/或AMPAR功能减弱是一致的，尽管这些受体的细胞总水平似乎是正常的。根据我们之前的工作，我们假设，这些大脑中的一个根本缺陷是突触中突触后密度的离子亲电受体复合体的异常处理，而前向运输的证据是在细胞内自稳驱动的，以克服这一缺陷。在这项应用中，我们建议使用精神分裂症患者和对照组的尸脑样本，以确定我们的发现对NMDA和AMPAR以及额叶皮质的特异性；确定与谷氨酸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；检测与运输和突触靶向相关的细胞内蛋白质和翻译后修饰；并直接检测这些受体在突触后密度和其他突触周围区域的表达。这些数据将使我们能够测试我们的精神分裂症模型与树突棘中谷氨酸受体动力学的异常有关。

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.