Thalamic Glutamate Dysregulation in Schizophrenia

描述（由申请人提供）：本项目旨在检测精神分裂症患者和对照组丘脑中谷氨酸受体和相关相互作用蛋白的表达。越来越多的证据表明，精神分裂症患者的海马能神经传递存在区域特异性改变，特别是在前额叶和扣带皮层以及海马。最近的尸检和影像学研究也涉及丘脑，一个区域拥有显着的丘脑能传出和传入连接上述脑区之间。强调正常丘脑功能的潜在重要性是其在处理感觉信息和调节意识中的作用，这些神经过程可能在精神分裂症中发生改变。精神分裂症的谷氨酸假说得到了药理学证据的支持，表明NMDA受体的参与，我们以前已经证明了这种疾病中丘脑中NMDA受体化学计量的变化。突触后NMDA受体复合物还包括谷氨酸受体相互作用蛋白，其对于正常受体组装、运输、插入质膜和活化至关重要。此外，AMPA受体的共定位和刺激特异性激活是启动长时程增强和其他NMDA受体介导的神经可塑性相关性所必需的。因此，我们推测，有异常的NMDA和/或AMPA受体的表达，以及异常的谷氨酸受体相互作用蛋白与突触后受体信号复合物在丘脑中的精神分裂症。因此，我们将研究这些分子在精神分裂症患者和对照组的死后大脑样本中的表达。我们建议检查NMDA和AMPA受体亚基的mRNA和蛋白质表达，以及已被确定为与这些受体相互作用的蛋白质。虽然已经积累的证据支持精神分裂症中的多巴胺能神经传递障碍的概念，但大多数以前的研究范围有限，通常集中在单个分子和单个基因表达水平上。我们建议进行详细的检查功能相关的分子在突触后受体复合物，通过测量转录和蛋白质水平表达在功能不同的丘脑核。此外，我们将进行细胞水平的研究，这将允许内在GABA能神经元和多巴胺能中继神经元的mRNA表达的变化进行比较。在这一组实验的结论，我们将有一个更清晰的了解与突触后NMDA受体复合物在丘脑中的精神分裂症的蛋白质的分子表达。对丘脑谷氨酸突触中神经传递关键分子的表达进行检查将突出异常，这些异常可以更有利地针对这种致残性疾病产生新的治疗方式。

DESCRIPTION (provided by applicant): This project is designed to examine the expression of glutamate receptors and related interacting proteins in the thalamus from patients with schizophrenia and a comparison group. Converging lines of evidence indicate that there are region specific alterations in glutamatergic neurotransmission in schizophrenia, particularly in the prefrontal and cingulate cortex, and hippocampus. Recent postmortem and imaging studies have also implicated the thalamus, a region possessing significant glutamatergic efferent and afferent connections between the aforementioned brain regions. Highlighting the potential importance of normal thalamic function are its roles in processing of sensory information and regulation of consciousness, neural processes that may be altered in schizophrenia. The glutamate hypothesis of schizophrenia is supported by pharmacological evidence suggesting involvement of the NMDA receptor, and we have previously demonstrated changes in NMDA receptor stoichiometry in thalamus in this illness. The postsynaptic NMDA receptor complex also includes glutamate receptor interacting proteins that are critical for normal receptor assembly, trafficking, insertion in the plasma membrane, and activation. In addition, colocalization and stimulus specific activation of AMPA receptors are required for initiation of long term potentiation and other NMDA receptor-mediated correlates of neuroplasticity. Thus, we hypothesize that there are abnormalities in the expression of the NMDA and/or AMPA receptors, as well as abnormalities of glutamate receptor interacting proteins associated with the postsynaptic receptor signaling complex in the thalamus in schizophrenia. Accordingly, we will examine the expression of these molecules in postmortem brain samples from schizophrenics and controls. We propose to examine mRNA and protein expression for NMDA and AMPA receptor subunits, as well as proteins that have been identified as interacting partners with these receptors. While evidence has accumulated to support the concept of a disturbance of glutamatergic neurotransmission in schizophrenia, most previous studies have been limited in scope, often focusing on a single molecule and a single level of gene expression. We propose to conduct a detailed examination of functionally linked molecules in the postsynaptic receptor complex, by measuring transcript and protein levels expressed in functionally distinct thalamic nuclei. Further, we will perform cell level studies that will permit comparisons of changes in mRNA expression by intrinsic GABAergic neurons and glutamatergic relay neurons. At the conclusion of this set of experiments, we will have a clearer understanding of the molecular expression of proteins associated with the postsynaptic NMDA receptor complex in the thalamus in schizophrenia. Examination of the expression of these molecules critical for neurotransmission in the thalamic glutamate synapse will highlight abnormalities that can be more profitably targeted for the generation of novel treatment modalities for this disabling illness.