Project Details
Projekt
Microglial diversity in the remodeling of GABAergic synapses in corticolimbic circuits and anxiety-related behaviors
Applicant
Professorin Dr. Dilja Krueger-Burg
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 559420174
Microglia play an extraordinarily wide range of roles in shaping brain function both under physiological and pathological conditions. As the resident macrophages of the central nervous system, they contribute to the response of the brain to infection and tissue damage, exacerbating or mitigating the effects of the damage depending on the context of the local environment. However, microglia play an equally critical role in shaping brain circuits under normal physiological conditions, particularly during early development as well as during periods of plasticity in mature circuits. Given the fundamental importance of these processes for normal brain function, it is unsurprising that, in recent years, altered microglial activity has been increasingly linked to the etiology of psychiatric disorders. It has been postulated that microglia may contribute to these disorders either through aberrant activation and inflammatory responses, potentially induced by stress, or due to loss of normal physiological processes that shape and maintain healthy brain circuits. One key process mediated by microglia under both physiological and pathological conditions in synapse remodeling, either through phagocytosis and pruning of synapses, or through stimulation of synapse formation. While most studies investigating synaptic remodeling by microglia have focused on their role at glutamatergic, excitatory synapses, recent evidence indicates that that they contribute equally to the remodeling of GABAergic inhibitory synapses. This observation is particularly relevant in light of the fact that GABAergic synapse dysfunction is also known to contribute to psychiatric disorders, including anxiety disorders. Uncovering the precise mechanisms by which microglia shape GABAergic synapses in the relevant brain regions, including the corticolimbic system, is therefore essential for understanding their role in the pathophysiology and potential treatment of psychiatric disorders. Based on this notion, the central objective of the current proposal is to determine whether microglia may contribute to the etiology of anxiety-related disorders through their role in remodeling of GABAergic synapses in the developing corticolimbic system, and to investigate whether the local environment influences microglial remodeling of GABAergic synapses under physiological and stress-induced pathological conditions. To this end, we will combine a wide range of approaches in mouse models, including immunohistochemistry, electrophysiology, optogenetics, chemogenetics, RNA sequencing and in vivo imaging to assess the influence of the local environment on microglial remodeling of GABAergic synapses in the developing corticolimbic system, investigate the molecular mechanisms by which GABAergic synaptic activity regulates microglial state under different local conditions, and determine the role of GABA-sensing microglia at GABAergic synapses and on anxiety-related avoidance behaviors.
DFG Programme
Priority Programmes
