Targeting C1q prevents microglia-mediated synaptic removal in neuropathic pain

Noosha Yousefpour, Shannon N. Tansley, Samantha Locke, Behrang Sharif, Marc Parisien, Farin B. Bourojeni, Haley Deamond, Vidhu Mathur, Nia Rahman-Khan Arana, Jean Sebastien Austin, Valerie Bourassa, Chengyang Wang, Valérie C. Cabana, Calvin Wong, Kevin C. Lister, Rose Rodrigues, Manon St-Louis, Marie-Eve Paquet, Michael C. Carroll, Yaisa Andrews-Zwilling, Philippe Seguela, Artur Kania, Ted Yednock, Jeffrey S. Mogil, Yves Koninck, Luda Diatchenko, Arkady Khoutorsky and Alfredo Ribeiro-da-Silva ()
Additional contact information
Noosha Yousefpour: McGill University
Shannon N. Tansley: McGill University
Samantha Locke: McGill University
Behrang Sharif: McGill University
Marc Parisien: McGill University
Farin B. Bourojeni: McGill University
Haley Deamond: McGill University
Vidhu Mathur: Annexon Biosciences
Nia Rahman-Khan Arana: Annexon Biosciences
Jean Sebastien Austin: McGill University
Valerie Bourassa: McGill University
Chengyang Wang: McGill University
Valérie C. Cabana: McGill University
Calvin Wong: McGill University
Kevin C. Lister: McGill University
Rose Rodrigues: McGill University
Manon St-Louis: McGill University
Marie-Eve Paquet: Université Laval
Michael C. Carroll: Harvard Medical School and Boston Children’s Hospital
Yaisa Andrews-Zwilling: Annexon Biosciences
Philippe Seguela: McGill University
Artur Kania: McGill University
Ted Yednock: Annexon Biosciences
Jeffrey S. Mogil: McGill University
Yves Koninck: McGill University
Luda Diatchenko: McGill University
Arkady Khoutorsky: McGill University
Alfredo Ribeiro-da-Silva: McGill University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Activation of spinal microglia following peripheral nerve injury is a central component of neuropathic pain pathology. While the contributions of microglia-mediated immune and neurotrophic signalling have been well-characterized, the phagocytic and synaptic pruning roles of microglia in neuropathic pain remain less understood. Here, we show that peripheral nerve injury induces microglial engulfment of dorsal horn synapses, leading to a preferential loss of inhibitory synapses and a shift in the balance between inhibitory and excitatory synapse density. This synapse removal is dependent on the microglial complement-mediated synapse pruning pathway, as mice deficient in complement C3 and C4 do not exhibit synapse elimination. Furthermore, pharmacological inhibition of the complement protein C1q prevents dorsal horn inhibitory synapse loss and attenuates neuropathic pain. Therefore, these results demonstrate that the complement pathway promotes persistent pain hypersensitivity via microglia-mediated engulfment of dorsal horn synapses in the spinal cord, revealing C1q as a therapeutic target in neuropathic pain.

Date: 2025
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DOI: 10.1038/s41467-025-59849-1

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