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

• Applicant: Professor Dr. Jochen W. Herms, since 1/2023
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403161218

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.

• DFG Programme: Research Units
• Subproject of: FOR 2858: Role of translocator protein (18 kDa) (TSPO) as a diagnostic and therapeutic target in the nervous system
• Ehemaliger Antragsteller: Mario M. Dorostkar, Ph.D., until 1/2023