PROJECT 2: CORTICAL GLUTAMATE SYNAPSE IN DEPRESSION

项目 2：抑郁症中的皮质谷氨酸突触

• 批准号: 8360507
• 负责人: Beata Karolewicz
• 金额: $ 21.41万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360507
• 关键词: Antidepressive Agents; Area; Astrocytes; Autopsy; Biochemical; Brain; Brain region; Cell Count; Cell Density; Chronic stress; Drug Delivery Systems; Enzymes; Exposure to; Fluoxetine; Freezing; Functional disorder; Funding; Glutamate Receptor; Glutamate Transporter; Glutamate-Ammonia Ligase; Glutamates; Goals; Grant; Human; Laboratory Animals; Lead; Major Depressive Disorder; Measures; Mental Depression; Metabolic; Metabolism; Modeling; Molecular; National Center for Research Resources; Neuroglia; Neurons; Neurosciences; Pathology; Prefrontal Cortex; Principal Investigator; Proteins; Rattus; Recycling; Reporting; Research; Research Infrastructure; Resources; Scaffolding Protein; Signal Transduction; Source; Synapses; System; Trees; United States National Institutes of Health; Up-Regulation; base; cellular pathology; cost; density; extracellular; hippocampal pyramidal neuron; improved; insight; molecular pathology; neuronal circuitry; nonhuman primate; novel; postsynaptic; receptor; restraint stress; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent research provides evidence for a dysfunction of the glutamate system in major depressive disorder (MDD). Our postmortem studies demonstrate that MDD is associated with altered concentrations of proteins involved in glutamate signaling. Despite significant evidence for abnormal glutamatergic signaling in MDD, the molecular mechanisms that contribute to these abnormalities at the level of cortical glutamate synapses have not yet been characterized. Glutamate is a critical component of neuronal circuitry in the prefrontal cortex (PFC), a brain area where cellular pathology has been detected consistently in MDD. Previous cell counting studies revealed reductions in the density and size of neuronal and glial cells in the PFC in MDD (see Project 1- Rajkowska). Since both astrocytes and pyramidal neurons are involved in the uptake, metabolism, and recycling of glutamate we hypothesize that : 1) glutamate transporters, metabolic enzymes, and receptors will be altered in the prefrontal cortex in MDD, and 2) these alterations will correlate with reductions in the densities of astrocytes and pyramidal neurons. Consistent with our hypothesis we speculate that glutamatergic pathology in the PFC will be associated with decreased levels of glial and neuronal glutamate transporters, decreased expression of glutamine synthetase and up-regulation of postsynaptic glutamate receptors and their scaffolding protein (Aim 1and 2). To achieve these goals we will utilize frozen cortical sections from the same subjects as those used in previous studies of cell density. It has been proposed that deficit in astrocytes and pyramidal neurons reported in postmortem studies may be the consequence of enhanced glutamate signaling in MDD. Interestingly, in laboratory animals, extracellular glutamate levels are increased after exposure to stress and chronic restraint stress induces shrinkage in dendritic trees of glutamatergic pyramidal neurons in the PFC. Thus, we further hypothesize that chronic stress will lead to abnormalities in glutamate signaling markers in rats that may resemble the abnormalities observed in MDD in postmortem studies. Therefore, application of restraint stress model (Aim 3) will provide important insight into the possible basis for glutamatergic abnormalities reported in human postmortem studies. To determine that the biochemical changes in depression are not resulting from the possible confounding influence of antidepressant treatment, human glutamate markers (Aim 1 and 2) will be compared to identical biochemical measures conducted in the comparable brain region of non-human primates treated with either fluoxetine or its vehicle (Aim 4). The studies proposed here will improve our understanding of the cellular and molecular pathology in depression, particularly as it relates to glutamate and may lead to the discovery of novel antidepressant drug targets and improved treatment for depression.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 最近的研究提供了证据表明，谷氨酸系统功能障碍的严重抑郁症（MDD）。我们的尸检研究表明，MDD与谷氨酸信号转导相关的蛋白质浓度改变有关。尽管有大量证据表明MDD中谷氨酸能信号异常，但在皮质谷氨酸突触水平导致这些异常的分子机制尚未得到表征。 谷氨酸是前额叶皮层（PFC）神经元回路的重要组成部分，该脑区在MDD中一直检测到细胞病理学。先前的细胞计数研究显示MDD患者PFC中神经元和神经胶质细胞的密度和大小减少（见项目1- Rajkowska）。 由于星形胶质细胞和锥体神经元都参与谷氨酸的摄取、代谢和再循环，我们假设：1）MDD患者前额叶皮层中的谷氨酸转运蛋白、代谢酶和受体将发生改变，2）这些改变将与星形胶质细胞和锥体神经元密度的降低相关。与我们的假设一致，我们推测PFC中的谷氨酸能病理学与神经胶质和神经元谷氨酸转运体水平降低、谷氨酰胺合成酶表达降低以及突触后谷氨酸受体及其支架蛋白的上调相关（目的1和2）。为了实现这些目标，我们将利用冷冻皮质切片从相同的科目中使用的细胞密度的研究。 有人提出，缺陷的星形胶质细胞和锥体神经元在死后的研究报告可能是结果增强谷氨酸信号在MDD。 有趣的是，在实验室动物中，细胞外谷氨酸水平增加后，暴露于压力和慢性束缚应激诱导收缩的树突状树的apmamatergic锥体神经元在PFC。因此，我们进一步假设，慢性应激将导致异常的谷氨酸信号标记物在大鼠中，可能类似于在MDD在尸检研究中观察到的异常。因此，束缚应激模型（目标3）的应用将为人类死后研究中报告的谷氨酸能异常的可能基础提供重要见解。 为了确定抑郁症中的生化变化不是由抗抑郁药治疗的可能混杂影响引起的，将人谷氨酸标志物（目的1和2）与在接受氟西汀或其溶媒（目的4）治疗的非人灵长类动物的可比脑区中进行的相同生化测量进行比较。本文提出的研究将提高我们对抑郁症细胞和分子病理学的理解，特别是因为它与谷氨酸有关，并可能导致发现新的抗抑郁药物靶点和改善抑郁症的治疗。