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: 8167933
• 负责人: Beata Karolewicz
• 金额: $ 20.65万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167933
• 关键词: Antidepressive Agents; Area; Astrocytes; Autopsy; Biochemical; Brain; Brain region; Cell Count; Cell Density; Chronic stress; Computer Retrieval of Information on Scientific Projects Database; Drug Delivery Systems; Enzymes; Exposure to; Fluoxetine; Freezing; Functional disorder; Funding; Glutamate Receptor; Glutamate Transporter; Glutamate-Ammonia Ligase; Glutamates; Goals; Grant; Human; Institution; Laboratory Animals; Lead; Major Depressive Disorder; Measures; Mental Depression; Metabolic; Metabolism; Modeling; Molecular; Neuroglia; Neurons; Pathology; Prefrontal Cortex; Proteins; Rattus; Recycling; Reporting; Research; Research Personnel; Resources; Scaffolding Protein; Signal Transduction; Source; Synapses; System; Trees; United States National Institutes of Health; Up-Regulation; base; cellular pathology; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 最近的研究为严重抑郁障碍(MDD)的谷氨酸系统功能障碍提供了证据。我们的尸检研究表明，MDD与参与谷氨酸信号转导的蛋白质浓度改变有关。尽管有大量证据表明MDD中存在谷氨酸能信号的异常，但在皮质谷氨酸突触水平上导致这些异常的分子机制尚未确定。谷氨酸是前额叶皮质(PFC)神经元电路的关键组成部分，前额叶皮质是MDD患者细胞病理一致的脑区。以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患者前额叶皮质的谷氨酸转运体、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的谷氨酸能病理与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减少以及突触后谷氨酸受体及其支架蛋白上调有关(目标1和2)。为了实现这些目标，我们将使用与先前细胞密度研究中使用的相同对象的冰冻皮质切片。 死后研究发现星形胶质细胞和锥体神经元的缺失可能是MDD谷氨酸信号增强的结果。有趣的是，在实验动物中，应激后细胞外谷氨酸水平增加，慢性束缚应激导致前额叶谷氨酸能锥体神经元树突树萎缩。因此，我们进一步假设，慢性应激将导致大鼠谷氨酸信号标志物的异常，这可能类似于在死后研究中观察到的MDD的异常。因此，束缚应激模型(AIM 3)的应用将为人类身体研究中报告的谷氨酸能异常的可能基础提供重要的见解。 为了确定抑郁症中的生化变化不是由抗抑郁药物治疗可能产生的混杂影响造成的，我们将把人类谷氨酸标志物(目标1和2)与在服用氟西汀或其载体(目标4)的非人类灵长类动物的可比脑区域中进行的相同生化指标进行比较。本文提出的研究将提高我们对抑郁症的细胞和分子病理学的理解，特别是与谷氨酸有关的抑郁症，并可能导致发现新的抗抑郁药物靶点和改进抑郁症的治疗。