Thalamic Glutamate Dysregulation in Schizophrenia

精神分裂症的丘脑谷氨酸失调

• 批准号: 6872773
• 负责人: JAMES H MEADOR-WOODRUFF
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872773
• 关键词: AMPA receptors; NMDA receptors; animal old age; antipsychotic agents; behavioral /social science research tag; biological signal transduction; brain metabolism; drug administration rate /duration; glutamates; haloperidol; intermolecular interaction; intracellular; laboratory rat; mental disorder chemotherapy; neuropsychology; neurotransmitter metabolism; neurotransmitter transport; protein protein interaction; protein structure function; receptor binding; receptor expression; schizophrenia; thalamic nuclei; thalamus; western blottings

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.

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，精神分裂症患者的谷氨酸能神经传递存在特定区域的改变，特别是在前额叶和扣带皮层以及海马体。最近的尸检和成像研究也涉及到丘脑，这是一个在上述大脑区域之间具有重要的谷氨酸输出和传入连接的区域。强调正常丘脑功能的潜在重要性是它在处理感觉信息和调节意识中的作用，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NMDA受体参与的药理学证据的支持，我们之前已经证明了这种疾病中丘脑NMDA受体化学计量的变化。突触后NMDA受体复合体还包括谷氨酸受体相互作用蛋白，这些蛋白对正常受体组装、运输、插入质膜和激活至关重要。此外，AMPA受体的共定位和刺激特异性激活是启动长期增强和其他NMDA受体介导的神经可塑性相关的必要条件。因此，我们假设精神分裂症患者的丘脑中存在NMDA和/或AMPA受体的异常表达，以及与突触后受体信号复合体相关的谷氨酸受体相互作用蛋白的异常。因此，我们将在精神分裂症患者和对照组的死后脑样本中检测这些分子的表达。我们建议检测NMDA和AMPA受体亚基的mRNA和蛋白表达，以及已确定与这些受体相互作用的蛋白。虽然有越来越多的证据支持精神分裂症中谷氨酸能神经传递障碍的概念，但大多数先前的研究范围有限，往往集中在单个分子和单个水平的基因表达上。我们建议通过测量在功能不同的丘脑核中表达的转录物和蛋白质水平，对突触后受体复合体中功能连接的分子进行详细的检查。此外，我们将进行细胞水平的研究，以比较内源性gaba能神经元和谷氨酸能接力神经元mRNA表达的变化。通过这组实验，我们将对精神分裂症丘脑突触后NMDA受体复合物相关蛋白的分子表达有更清晰的认识。检查丘脑谷氨酸突触中这些对神经传递至关重要的分子的表达将突出异常，这些异常可以更有利地针对这种致残疾病的新治疗方式的产生。