guest ::
| Home > Documents in Process > Mechanisms of microglia-mediated synapse formation and elimination |
| Home > Documents in Process > Mechanisms of microglia-mediated synapse formation and elimination |
| Dissertation / PhD Thesis | DZNE-2025-01172 |
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.
|
The record appears in these collections: |
PDF
PDF (PDFA)