GLUTAMATE SYNAPSE ABNORMALITIES IN SCHIZOPHRENIC CORTEX

精神分裂症皮层谷氨酸突触异常

• 批准号: 6266218
• 负责人: JAMES H MEADOR-WOODRUFF
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6266218
• 关键词: NMDA receptors; autoradiography; binding sites; cingulate gyrus; dopamine receptor; gene expression; glutamate receptor; glutamates; human genetic material tag; human tissue; immunologic assay /test; in situ hybridization; membrane transport proteins; messenger RNA; neocortex; neural information processing; neural transmission; neuroanatomy; neurochemistry; postmortem; receptor binding; receptor expression; schizophrenia; synapses; western blottings

DESCRIPTION: (Adapted from applicant's abstract)This project is designed to examine the expression of proteins associated with glutamate neurotransmission in the prefrontal and cingulate cortex of autopsy-obtained brain tissue from schizophrenic patients and matched controls. Converging evidence indicates that there are abnormalities of glutamatergic neurotransmission in specific brain regions in schizophrenia. While pharmacological evidence suggests involvement of the NMDA receptor in this illness, other studies and theoretical considerations suggest that other molecules associated with glutamatergic transmission may be abnormal in schizophrenia. The investigators hypothesize that there are abnormalities in the expression of the genes associated with the glutamate synapse in the limbic neocortex in schizophrenia. Accordingly, this project will examine the expression of these molecules in postmortem brain samples from schizophrenics and controls. The investigators propose to examine the proteins associated with the glutamate synapse in a comprehensive fashion, by (1) examining the expression of receptors, transporters, and anchoring proteins critical for glutamatergic neurotransmission; and (2) determining their expression at multiple levels of gene expression and organization, by determining the expression of the mRNAs encoding each, as well as protein levels, and higher order levels of protein organization as reflected by specific binding sites. While some evidence has accumulated to support the concept of a disturbance in glutamatergic transmission in schizophrenia, most previous studies have been limited in scope, often focusing on a single molecule in a discrete region of the brain. The investigators propose to conduct a comprehensive examination of the glutamate synapse in schizophrenia, by examining the expression of each molecule at multiple levels of molecular genetic organization. Further, the investigators will do this in the same brains, allowing meaningful comparisons within a given brain. At the conclusion of this set of experiments, the investigators will have a clearer understanding of the molecular genetic expression of the proteins associated with the glutamate synapse in schizophrenia at multiple levels of gene expression. Examination of the expression of these proteins critical for neurotransmission at the limbic cortical glutamate synapse may highlight abnormalities which can be more profitably targeted for novel treatment of this disabling illness.

描述：(改编自申请者的摘要)本项目旨在 检测谷氨酸神经传递相关蛋白的表达 在尸检获得的脑组织的前额叶和扣带回皮质中 精神分裂症患者和匹配的对照组。不断有证据表明 在特定的脑内存在谷氨酸能神经传递的异常 精神分裂症的区域。虽然药理学证据表明 NMDA受体在这种疾病中的作用，其他研究和理论 考虑到与谷氨酸能有关的其他分子 精神分裂症的传播可能是异常的。调查人员的假设是 与此相关的基因表达存在异常 精神分裂症边缘新皮质中的谷氨酸突触。因此，这 该项目将研究这些分子在死后大脑中的表达 精神分裂症患者和对照组的样本。调查人员提议检查 与谷氨酸突触相关的蛋白质， 通过(1)检测受体、转运体和锚定的表达 谷氨酸能神经传递的关键蛋白质；以及(2)测定 它们在基因表达和组织的多个水平上的表达，通过 确定编码每一个的mRNAs以及蛋白质的表达 水平，以及更高级别的蛋白质组织，如 特定的结合部位。虽然已经积累了一些证据来支持 精神分裂症患者谷氨酸能传递障碍的概念 以前的研究在范围上是有限的，往往集中在单一的 分子位于大脑的一个离散区域。调查人员提议 对精神分裂症患者的谷氨酸突触进行全面检查， 通过检测每个分子在多个分子水平上的表达 基因组织。此外，调查人员将以同样的方式完成这项工作 大脑，允许在给定的大脑内进行有意义的比较。在结束时 对这套实验，调查人员会有更清晰的认识 与之相关的蛋白质的分子遗传表达 精神分裂症患者谷氨酸突触在多水平的基因表达。 检测这些对神经传递至关重要的蛋白质的表达 在边缘皮质谷氨酸突触可能突出异常，这可能 将更有利可图的目标对准这种致残疾病的新疗法。