Center for Neuropathology: Neuroscience / Neuropharmacology (Herms)

Project description

Project description: Microglia constantly monitor and interact with synapses in the resting state. Upon activation, microglia modulate synaptic plasticity and function by eliminating particular subsets of synaptic structures (e.g. dendritic spines). We previously observed that upon activating microglial 18 kDa translocator protein (TSPO), microglia alter morphology and start excessively engulfing synaptic materials, causing synaptic loss and cognitive decline in wild-type (WT) mice (see Shi et al., Nat Neurosci 2022). As a target of interest, ligand-driven modulation of TSPO has been extensively studied, and previous studies have demonstrated the therapeutic effects of these selected TSPO ligands in mouse models and clinical trials. However, the underlying mechanisms of these effects, especially how these ligands affect microglia-synapse structural interactions and subsequent microglial synaptic elimination via TSPO, require more evidence to be elucidated. The proposed project will be carried out using a series of state-of-art methods, e.g. intravital multiphoton microscopy, super-resolution confocal microscopy and 3D reconstruction for multidimensional quantification and analysis of the microglial structure and synaptic elimination. The project will not only fill this gap by yielding evidence on how different types of TSPO ligands affect microglia and synapses but also deepen our understanding of TSPO per se in physiology, which may subsequently inspire more TSPO-based therapeutic strategies in disease conditions such as neuroinflammation and neurodegenerative diseases.