CORTICAL GLUTAMATE SYNAPSE IN 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。 大量研究为重度抑郁障碍(MDD)患者大脑谷氨酸信号系统功能障碍提供了令人信服的支持性证据。这一假设是基于(1)体内成像技术显示主要抑郁症受试者大脑中谷氨酸水平异常的证据；(2)抑郁症中参与谷氨酸传递的蛋白质的免疫反应改变的尸检证据；(3)在实验室动物和人类中看到的减少谷氨酸信号转导的药物的抗抑郁作用。 我们使用死后人脑组织进行的初步研究提供了MDD受试者脑干谷氨酸能信号指标异常的证据。结合其他实验室的研究，我们的初步发现表明，MDD中异常的谷氨酸能神经元活动可以通过死后脑中的神经化学异常来揭示。大脑的一个区域，谷氨酸是神经元回路的关键组成部分，在MDD中重现了粗略的神经病理学，这就是海马体。据报道，MDD受试者的海马体体积和神经纤维减少。有趣的是，在实验动物中，暴露在压力下的大脑谷氨酸水平会增加，而长期的压力会导致海马体萎缩。 基于这些发现和我们的初步数据，我们假设MDD海马区的至少部分病理是由谷氨酸信号升高触发的。这种升高的信号将通过海马区谷氨酸指数的异常来揭示，如谷氨酸转运体、受体及其细胞内相关分子。为了实现这些目标，将利用MDD受试者的死后脑组织和精心匹配的精神正常对照。诊断是在克雷格·斯托克迈尔医生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。

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 brains 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.