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

小胶质细胞和被称为炎症介质的蛋白质，例如补体级联组分，参与突触的生理去除，这一过程称为突触修剪。这个过程发生在青春期以及学习和记忆期间，是突触重塑的一部分。此外，中枢神经系统中小胶质细胞的活化和炎性改变是许多神经退行性疾病如阿尔茨海默病和帕金森病的突出特征。我们假设，在这些条件下，慢性小胶质细胞激活导致突触的病理性丧失，由于这些生理机制的异常激活。提示在青春期导致脑区域特异性突触丢失的类似机制发生在精神病中。TSPO的小胶质细胞表达增加是脑炎症的典型标志，这也已在神经退行性疾病中发现。在初步的实验中，我们表明，激活TSPO导致减少兴奋性突触后，即使在没有炎症。此外，药理学调制TSPO活动在帕金森氏病的小鼠模型中废除了皮层兴奋性postsynapses.As的损失本项目的第一部分，我们计划研究TSPO配体和TSPO活动的突触密度和营业额在生理条件下使用体内多光子成像和离体共聚焦成像的效果。我们将使用小胶质细胞特异性TSPO敲除动物来了解小胶质细胞活性和小胶质细胞TSPO在生理突触转换中的作用。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敲除和TSPO活性的药理学调节的影响。通过这些手段，我们将测试TSPO是否构成用于治疗突触丧失的有希望的药物靶标，突触丧失代表神经退行性疾病中认知下降的结构相关性。与项目C4合作，我们将进一步研究TSPO调节在应激和焦虑动物模型中对突触可塑性的影响。最后，我们的目标是使用RNASeq对分离的小胶质细胞进行研究，以研究治疗和未治疗的阿尔茨海默病和帕金森病动物模型中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途径的进一步细节，这些途径可能是这些疾病的药物治疗的靶点。

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.