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@PHDTHESIS{Gockel:281739,
      author       = {Gockel, Nala Eileen},
      title        = {{M}echanisms of microglia-mediated synapse formation and
                      elimination},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      reportid     = {DZNE-2025-01172},
      pages        = {112 pp.},
      year         = {2025},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2025},
      abstract     = {Early 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.},
      cin          = {AG Fuhrmann},
      cid          = {I:(DE-2719)1011004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)11},
      url          = {https://pub.dzne.de/record/281739},
}