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Real-time mechanisms of exacerbated synaptic remodeling by microglia in acute models of systemic inflammation and
Carla Cangalaya1, Susanne Wegmann2, Weilun Sun3
1German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Institut für Biochemie und Zellbiologie, Otto-von-Guericke-University, Medical Faculty, Magdeburg, Germany; ESF International Graduate School on Analysis, Imaging and Modelling of Neuronal and Inflammatory Processes, Magdeburg, Germany.
Abstract:
Remodeling of synapses by microglia is essential for synaptic plasticity in the brain. However, during neuroinflammation and neurodegenerative diseases, microglia can induce excessive synaptic loss, although the precise underlying mechanisms are unknown. To directly observe microglia-synapse interactions under inflammatory conditions, we performed in vivo two-photon time-lapse imaging of microglia-synapse interactions after bacterial lipopolysaccharide administration to model systemic inflammation, or after inoculation of Alzheimer's disease (AD) brain extracts to model disease-associated neuroinflammatory microglial response. Both treatments prolonged microglia-neuron contacts, decreased basal surveillance of synapses and promoted synaptic remodeling in response to synaptic stress induced by focal single-synapse photodamage. Spine elimination correlated with the expression of microglial complement system/phagocytic proteins and the occurrence of synaptic filopodia. Microglia were observed contacting spines, then stretching and phagocytosing spine head filopodia. Thus, in response to inflammatory stimuli microglia exacerbated spine remodeling through prolonged microglial contact and elimination of spines 'tagged' by synaptic filopodia.
Insights
Microglia
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are crucial for synaptic plasticity.
- Neuroinflammation and neurodegenerative diseases involve excessive synaptic loss mediated by microglia.
- The precise mechanisms of microglia-induced synaptic loss remain unclear.
Purpose of the Study:
- To directly observe microglia-synapse interactions under inflammatory conditions.
- To elucidate the mechanisms by which microglia contribute to synaptic loss during inflammation and Alzheimer's disease.
Main Methods:
- In vivo two-photon time-lapse imaging was employed.
- Microglia-synapse interactions were analyzed following bacterial lipopolysaccharide administration (systemic inflammation model).
- Interactions were also studied after inoculation with Alzheimer's disease brain extracts (disease-associated neuroinflammation model).
Main Results:
- Inflammatory stimuli prolonged microglia-neuron contacts and reduced basal synapse surveillance.
- Microglia promoted synaptic remodeling under stress, correlating spine elimination with complement/phagocytic protein expression.
- Microglia were observed extending and phagocytosing synaptic filopodia, leading to spine elimination.
Conclusions:
- Microglia exacerbate synaptic remodeling and loss in response to inflammatory stimuli.
- Prolonged microglia-neuron contact and elimination of 'tagged' spines are key mechanisms.
- These findings offer insights into synaptic dysfunction in neuroinflammation and Alzheimer's disease.
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