000281739 001__ 281739
000281739 005__ 20251013134308.0
000281739 037__ $$aDZNE-2025-01172
000281739 1001_ $$0P:(DE-2719)9002002$$aGockel, Nala Eileen$$b0$$udzne
000281739 245__ $$aMechanisms of microglia-mediated synapse formation and elimination
000281739 260__ $$c2025
000281739 300__ $$a112 pp.
000281739 3367_ $$2DataCite$$aOutput Types/Dissertation
000281739 3367_ $$2ORCID$$aDISSERTATION
000281739 3367_ $$2BibTeX$$aPHDTHESIS
000281739 3367_ $$02$$2EndNote$$aThesis
000281739 3367_ $$0PUB:(DE-HGF)11$$2PUB:(DE-HGF)$$aDissertation / PhD Thesis$$bphd$$mphd$$s1760355662_8169
000281739 3367_ $$2DRIVER$$adoctoralThesis
000281739 502__ $$aDissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, 2025$$bDissertation$$cRheinische Friedrich-Wilhelms-Universität Bonn$$d2025
000281739 520__ $$aEarly impairments at the synaptic level can lead to disruption of communication between neurons, triggering neurological diseases such as schizophrenia. Emerging evidence has identified microglia as a key player in shaping synaptic architecture, but the precise mechanisms remain insufficiently understood.This study aims to investigate mechanisms of microglia-mediated synapse formation and elimination in two physiological contexts: first, during postnatal development, targeting microglia-complement interactions and second, during adult homeostasis examining microglia-synapse crosstalk via neurotransmitter signaling.The first objective used two-photon in vivo imaging to assess changes in synaptic density, microglial surveillance dynamics and microglia-synapse contact rates in a mouse model of complement protein overexpression, recapitulating hallmark phenotypes of schizophrenia. A complement receptor knock-out demonstrated to mediate synaptic density deficits and deficiency in microglia-synapse contacts after upregulation of complement proteins, potentially via a lack in spine formation. Specifically, the microglial iC3b-CR3 pathway was identified as a potential therapeutic target in schizophrenia research.The second objective targeted microglia-presynapse communication in the adult hippocampus with a microglia specific knock-out of a cholinergic neurotransmitter receptor. Awake two-photon calcium imaging of presynaptic boutons in combination with microglial dynamics revealed high microglia surveillance of putative active boutons. This suggested possible activity-dependent synapse remodeling by microglia in the adult brain. Microglia motility in a cholinergic receptor knock-out was altered upon distinct stimulation paradigms of neuronal projections. This identified the microglial α7 nicotinic acetylcholine receptor as a potential modulator of structural synaptic plasticity by sensing excess neurotransmitter release.Lastly, two-photon STED imaging was introduced enabling high-resolution in vivo imaging of nanoscale structures offering potential for future insights into active microglial synapse formation and elimination.These findings suggest microglia to have a central role in modulating synaptic densities, both in development, as well as in adulthood, via complement and neurotransmitter signaling, in health and disease. Microglial heterogeneity and context-dependency highlighted the importance to maintain a homeostatic balance between neurons and microglia to prevent cognitive impairments throughout life.
000281739 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
000281739 8564_ $$uhttps://pub.dzne.de/record/281739/files/DZNE-2025-01172_Restricted.pdf
000281739 8564_ $$uhttps://pub.dzne.de/record/281739/files/DZNE-2025-01172_Restricted.pdf?subformat=pdfa$$xpdfa
000281739 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)9002002$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000281739 9131_ $$0G:(DE-HGF)POF4-352$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vDisease Mechanisms$$x0
000281739 9141_ $$y2025
000281739 9201_ $$0I:(DE-2719)1011004$$kAG Fuhrmann$$lNeuroimmunology and Imaging$$x0
000281739 980__ $$aphd
000281739 980__ $$aEDITORS
000281739 980__ $$aVDBINPRINT
000281739 980__ $$aI:(DE-2719)1011004
000281739 980__ $$aUNRESTRICTED