Project Details
Projekt
The role of microtubule cytoskeleton modulation in microglia and its effect on cognition
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Cognitive, Systems and Behavioural Neurobiology
Cognitive, Systems and Behavioural Neurobiology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500305540
Microglia are resident macrophages of the central nervous system (CNS), where they act as first immune response to pathogens. Moreover, microglia are highly motile cells that are associated with regulation of CNS homeostasis and neuronal function. However, how microglia influence neurons and vice versa is poorly understood. The cytoskeleton proteins “actin depolarizing factor” (ADF) and Cofilin-1 (Cfl1), which modulate the depolymerizing of actin filaments, are crucial in neuronal development, function and cell cycle control. We found that microglial ADF/Cfl1 are required for microglial scanning of the brain parenchyma, also called microglial fine process motility, and migration of microglia. ADF/Cfl1-deficient microglia in addition to altered F-actin dynamics, also showed aberrant microtubule dynamics. In the hippocampus, a brain region relevant for learning and memory, we revealed a relationship between microglial fine process motility and neuronal activity, as well as synapse stability. Interestingly, ADF/Cfl1-KO mice were impaired in hippocampus dependent learning and memory, indicating that ADF/Cfl1-deficiency in microglia affects cognition potentially via their function in regulating synapse stability and neuronal activity. Furthermore, since we found a deficit of microtubule dynamics, we were wondering whether microglial fine process motility depends on microtubule dynamics, impinging on neuronal function and cognition. Therefore, we hypothesize that microglia function depends on a dynamic microtubule cytoskeleton and that this is crucial for neuronal network function contributing to learning and memory. We will address this hypothesis by using mice with a microglia-specific and inducible knockout of tubulin tyrosine ligase (TTL), which is necessary for microtubule dynamics. In these mice, we will carry out cutting edge in vivo two-photon microscopy of neurons and microglia in the hippocampus of awake head-fixed and freely moving mice to decipher the role of microtubule dynamics in microglia and its importance for neuronal networks. To address how TTL-deficient microglia affect synapse remodeling, we will investigate dendritic spines and adjacent microglia in the hippocampus in vivo on the nanoscopic scale by cutting-edge 2P-STED microscopy. Our experiments will provide novel insights on the role of microtubules in microglia, and how this function influences learning and memory.
DFG Programme
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