Microglial extracellular vesicles mediate C1q deposition at the pre‐synapse and promote synaptic pruning

D'Arrigo, G, Cutugno, G, Golia, MT, Sironi, F, Lombardi, M, Colombo, SF, Frigerio, R, Cretich, M, Gagni, P, Battocchio, E, Barone, C, Azzoni, E, Bellini, S, Saraceno, C, Ghidoni, R, Bendotti, C, Paolicelli, RC, Gabrielli, M ORCID: https://orcid.org/0000-0003-4958-541X and Verderio, C, 2025. Microglial extracellular vesicles mediate C1q deposition at the pre‐synapse and promote synaptic pruning. Journal of Extracellular Vesicles, 14 (12): e70173. ISSN 2001-3078

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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.

Item Type:	Journal article
Publication Title:	Journal of Extracellular Vesicles
Creators:	D'Arrigo, G., Cutugno, G., Golia, M.T., Sironi, F., Lombardi, M., Colombo, S.F., Frigerio, R., Cretich, M., Gagni, P., Battocchio, E., Barone, C., Azzoni, E., Bellini, S., Saraceno, C., Ghidoni, R., Bendotti, C., Paolicelli, R.C., Gabrielli, M. and Verderio, C.
Publisher:	Taylor & Francis Open
Date:	15 December 2025
Volume:	14
Number:	12
ISSN:	2001-3078
Identifiers:	Number Type 10.1002/jev2.70173 DOI 2521244 Other
Rights:	This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	11 Nov 2025 09:34
Last Modified:	05 Jan 2026 12:52
URI:	https://irep.ntu.ac.uk/id/eprint/54701

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