GLUTAMATE SYSTEM IN DEPRESSION

谷氨酸系统处于抑郁状态

• 批准号: 7381919
• 负责人: Beata Karolewicz
• 金额: $ 14.39万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381919
• 关键词: GLUTAMATE; SYSTEM; DEPRESSION

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. A large amount of research provides compelling supportive evidence for a dysfunction in the brain¿s glutamate signaling system in major depressive disorder (MDD). This postulate is based on (1) evidence of abnormal level of glutamate in the brain of major depressive subjects as revealed by in vivo imaging techniques; (2) postmortem evidence of altered immunoreactivities of proteins engaged in glutamate transmission in depression; (3) antidepressant-like effects of agents decreasing glutamate signaling seen in laboratory animals and humans. Our preliminary investigations using postmortem human brain tissue have provided evidence of abnormalities in indices of glutamatergic signaling in the brainstem from subjects with MDD. In conjunction with research by other laboratories, our preliminary findings have demonstrated that abnormal glutamatergic neuronal activity in MDD can be revealed by neurochemical abnormalities in the postmortem brain. An area of the brain where glutamate is a critical component of neuronal circuitry and where gross neuropathology has been reproducibly demonstrated in MDD is the hippocampus. Reductions in hippocampal volume and neuropil have been reported for MDD subjects. Interestingly, in laboratory animals, brain glutamate levels are increased after exposure to stress and chronic stress produces hippocampal atrophy. Based on these findings and our preliminary data, we hypothesize that at least part of the pathology of the hippocampus in MDD is triggered by elevated glutamate signaling. This elevated signaling will be revealed by abnormalities in glutamate indices, such as glutamate transporters, receptors and their intracellular-associated molecules, in the hippocampus. To achieve these goals postmortem brain tissues from MDD subjects and carefully matched psychiatrically normal controls will be utilized. Diagnoses are made via a rigorous psychiatric autopsy program under the direction of Dr. Craig Stockmeier. Overall, the proposed research will elucidate the molecular underpinning of glutamate pathology and may yield new targets for novel therapeutic approaches to treatment of depressive disorders.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。大量研究为重度抑郁症 (MDD) 中大脑谷氨酸信号系统功能障碍提供了令人信服的支持证据。该假设基于（1）通过体内成像技术揭示的重度抑郁症受试者大脑中谷氨酸水平异常的证据； (2) 死后证据表明，抑郁症中参与谷氨酸传递的蛋白质的免疫反应性发生了改变； (3) 在实验动物和人类中观察到减少谷氨酸信号传导的药物的抗抑郁样作用。 我们使用死后人类脑组织进行的初步研究提供了重度抑郁症患者脑干谷氨酸信号指数异常的证据。与其他实验室的研究相结合，我们的初步研究结果表明，MDD 中谷氨酸能神经元的异常活动可以通过死后大脑中的神经化学异常来揭示。海马体是大脑中的一个区域，其中谷氨酸是神经元回路的关键组成部分，并且在重度抑郁症中，大体神经病理学已得到可重复证明。据报道，MDD 受试者的海马体积和神经纤维减少。有趣的是，在实验动物中，暴露于压力后大脑谷氨酸水平会增加，而慢性压力会导致海马萎缩。 根据这些发现和我们的初步数据，我们假设 MDD 中海马的病理学至少有一部分是由谷氨酸信号传导升高触发的。这种升高的信号传导将通过海马中谷氨酸指数的异常来揭示，例如谷氨酸转运蛋白、受体及其细胞内相关分子。为了实现这些目标，将使用MDD受试者的死后脑组织和仔细匹配的精神正常对照。诊断是在克雷格·斯托克梅尔博士的指导下通过严格的精神病学尸检程序进行的。 总体而言，拟议的研究将阐明谷氨酸病理学的分子基础，并可能为治疗抑郁症的新治疗方法产生新的靶点。