C3: The role of TSPO on dendritic spine structural plasticity in health and neurodegenerative diseases

C3：TSPO 对健康和神经退行性疾病中树突棘结构可塑性的作用

• 批准号: 422181340
• 负责人: Professor Dr. Jochen W. Herms, since 1/2023
• 金额: --
• 依托单位: Zentrum für Neuropathologie und Prionforschung
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422181340?language=en
• 关键词: C3; role; TSPO; dendritic; spine

Microglia and proteins known as mediators of inflammation, e.g. complement cascade components, are involved in the physiological removal of synapses, a process termed synaptic pruning. This process occurs as part of reshaping of synapses during adolescence as well as during learning and memory. Moreover, activation of microglia and inflammatory alterations in the central nervous system are prominent features of many neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. We hypothesize that chronic microglia activation in these conditions causes pathological loss of synapses due to aberrant activation of these physiological mechanisms. Similar mechanisms resulting in brain-region specific synapse loss during adolescence are suggested to occur in psychoses.Increased microglial expression of TSPO is a typical hallmark of brain inflammation, which has been found also in neurodegenerative diseases. In preliminary experiments we showed that activation of TSPO leads to a reduction of excitatory postsynapses even in the absence of inflammation. Furthermore, pharmacological modulation of TSPO activity in a mouse model of Parkinson’s disease abolished the loss of cortical excitatory postsynapses.As first part of this project we plan to study the effect of TSPO ligands and TSPO activity on synapse density and turnover under physiological conditions using in vivo multiphoton imaging and ex vivo confocal imaging. We will use microglia-specific TSPO knockout animals to understand the role of microglia activity and microglial TSPO in physiological synapse turnover. Subsequently, we plan to study the effects of microglial TSPO knockout and pharmacological modulation of TSPO activity in animal models of neurodegenerative diseases. By these means we will test whether TSPO constitutes a promising drug target for the treatment of synapse loss, which represents the structural correlate of cognitive decline in neurodegenerative diseases. In collaboration with project C4 we will further study the effects of TSPO modulation in animal models of stress and anxiety on synaptic plasticity.Finally, we aim to study the activation states of microglia in treated and untreated animal models of Alzheimer’s and Parkinson’s disease using RNASeq on isolated microglia. These results may reveal further details on the cellular mechanisms of microglia activation and novel pathways, which may be targeted by pharmacological treatment in these diseases.

小胶质细胞和被称为炎症介质的蛋白质，例如补体级联成分，参与了突触的生理性移除，这一过程被称为突触修剪。这一过程发生在青春期以及学习和记忆期间突触重塑的过程中。此外，中枢神经系统的小胶质细胞激活和炎性改变是许多神经退行性疾病的显著特征，如阿尔茨海默病和帕金森病。我们假设，在这些情况下，慢性小胶质细胞的激活会由于这些生理机制的异常激活而导致突触的病理性丧失。类似的机制导致青春期大脑区域特异性突触丢失被认为发生在精神病中。TSPO小胶质细胞表达增加是脑部炎症的典型标志，在神经退行性疾病中也发现了这种现象。在初步实验中，我们发现，即使在没有炎症的情况下，TSPO的激活也会导致兴奋性突触后减少。此外，在帕金森病小鼠模型中，TSPO活性的药理调节消除了皮质兴奋性突触后的丢失。作为本项目的第一部分，我们计划利用体内多光子成像和体外共聚焦成像研究在生理条件下TSPO配体和TSPO活性对突触密度和周转的影响。我们将使用小胶质细胞特异的TSPO基因敲除动物来了解小胶质细胞活性和小胶质细胞TSPO在生理性突触转换中的作用。随后，我们计划在神经退行性疾病的动物模型中研究小胶质细胞TSPO基因敲除和药物调节TSPO活性的作用。通过这些手段，我们将测试TSPO是否构成了治疗突触丢失的有前途的药物靶点，突触丢失代表了神经退行性疾病中认知功能下降的结构相关性。与C4项目合作，我们将进一步研究TSPO在应激和焦虑动物模型中对突触可塑性的调节作用。最后，我们的目标是使用RNAseq对分离的小胶质细胞进行研究，研究阿尔茨海默病和帕金森病动物模型中治疗和未治疗的小胶质细胞的激活状态。这些结果可能揭示小胶质细胞激活的细胞机制和新的途径的进一步细节，这可能是药物治疗这些疾病的靶点。