Microglial Extracellular Vesicles Mediate C1q Deposition at the Pre‐Synapse and Promote Synaptic Pruning
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.
Authors
- Martina Gabrielli (ORCID: https://orcid.org/0000-0003-4958-541X)
- Marta Lombardi (ORCID: https://orcid.org/0000-0001-6703-7121)
- Maria Teresa Golia (ORCID: https://orcid.org/0000-0002-8610-696X)
- Emanuele Azzoni (ORCID: https://orcid.org/0000-0002-4572-5692)
- Claudia Verderio (ORCID: https://orcid.org/0000-0001-7216-5873)
- Francesca Sironi (ORCID: https://orcid.org/0000-0001-5287-3784)
- Sonia Bellini (ORCID: https://orcid.org/0000-0002-6162-252X)
- Rosa Chiara Paolicelli (ORCID: https://orcid.org/0000-0001-6851-0849)
- Marina Cretich (ORCID: https://orcid.org/0000-0001-8251-5275)
- Paola Gagni (ORCID: https://orcid.org/0000-0002-3652-6173)
- Caterina Bendotti (ORCID: https://orcid.org/0000-0003-1055-1271)
- Elisabetta Battocchio (ORCID: https://orcid.org/0000-0001-7431-2224)
- Cristiana Barone (ORCID: https://orcid.org/0000-0001-5517-3214)
- Roberta Ghidoni (ORCID: https://orcid.org/0000-0002-7691-1957)
- Giulia D’Arrigo (ORCID: https://orcid.org/0000-0003-3984-8888)
- Sara Colombo (ORCID: https://orcid.org/0000-0001-9714-3961)
- Roberto Frigerio (ORCID: https://orcid.org/0000-0001-5855-7010)
- Claudia Saraceno (ORCID: https://orcid.org/0000-0001-8618-4282)
- Giulia Cutugno (ORCID: https://orcid.org/0009-0005-2142-6929)
Institutions
- Mario Negri Institute for Pharmacological Research (IT)
- Azienda Ospedaliera San Gerardo (IT)
- Construction Technologies Institute (IT)
- Neuroscience Institute (IT)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- National Research Council (IT)
- University of Milano-Bicocca (IT)
- University of Lausanne (CH)
Publication Details
- Journal
- Journal of Extracellular Vesicles
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1002/jev2.70173
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00