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Published on: February 5, 2018
Microglial Extracellular Vesicles Mediate C1q Deposition at the Pre-Synapse and Promote Synaptic Pruning
Giulia D'Arrigo1, Giulia Cutugno1, Maria Teresa Golia1
1Institute of Neuroscience, National Research Council of Italy, Vedano al Lambro, Italy.
Abstract:
C1q is released by microglia, localizes on weak synapses and acts as a tag for microglial synaptic pruning. However, how C1q tags synapses during the pruning period remains to be fully elucidated. Here, we report that C1q is delivered via extracellular vesicles by microglia to pre-synaptic sites that externalize phosphatidylserine. Using approaches to increase or reduce vesicles production in microglia, by C9orf72 knock out or pharmacological inhibition, respectively, we provided mechanistic evidence linking extracellular vesicle release to pre-synaptic remodelling in neuron-microglia cultures. In C9orf72 knockout mice, we confirmed larger production of microglial extracellular vesicles and showed augmented C1q presynaptic deposition associated with enhanced engulfment by microglia in the early postnatal hippocampus. Finally, we provide evidence that microglia physiologically release more vesicles during the period of postnatal circuit refinement. These findings implicate abnormal release of microglial extracellular vesicles in both neurodevelopmental and age-related disorders characterized by dysregulated microglia-mediated synaptic pruning.
Insights
Microglia release C1q via extracellular vesicles to tag synapses for pruning. This process, linked to C9orf72, is crucial for synaptic refinement and may be implicated in neurological disorders.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Microglia, the immune cells of the brain, play a critical role in synaptic pruning, a process essential for neural circuit development.
- C1q (Complement component 1q) is known to tag synapses for elimination by microglia, but the precise mechanism of this tagging is not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which C1q tags synapses for microglial pruning.
- To investigate the role of extracellular vesicles in C1q-mediated synaptic pruning.
Main Methods:
- Utilized neuron-microglia cultures with genetic (C9orf72 knockout) and pharmacological manipulations to alter microglial extracellular vesicle production.
- Examined C1q deposition and microglial engulfment in the hippocampus of C9orf72 knockout mice.
- Assessed extracellular vesicle release from microglia during postnatal circuit refinement.
Main Results:
- Demonstrated that microglia deliver C1q via extracellular vesicles to pre-synaptic sites that externalize phosphatidylserine.
- Mechanistically linked extracellular vesicle release to pre-synaptic remodeling.
- Observed increased microglial extracellular vesicle production and enhanced C1q presynaptic deposition in C9orf72 knockout mice.
- Showed increased microglial vesicle release during the critical period of postnatal circuit refinement.
Conclusions:
- Microglial extracellular vesicles are a key mechanism for delivering C1q to synapses, mediating synaptic pruning.
- Dysregulation of microglial extracellular vesicle release may contribute to neurodevelopmental and age-related disorders involving aberrant synaptic pruning.
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