Targeting C1q prevents microglia-mediated synaptic removal in neuropathic pain
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.
Authors
- Arkady Khoutorsky (ORCID: https://orcid.org/0000-0003-3846-8728)
- Vidhu Mathur
- Jeffrey S. Mogil (ORCID: https://orcid.org/0000-0003-1359-5720)
- Luda Diatchenko (ORCID: https://orcid.org/0000-0002-1350-6727)
- Calvin Wong (ORCID: https://orcid.org/0000-0001-7728-3035)
- Valérie C. Cabana
- Ted Yednock (ORCID: https://orcid.org/0000-0002-9637-8555)
- Shannon Tansley (ORCID: https://orcid.org/0000-0003-2387-3800)
- Yves De Koninck (ORCID: https://orcid.org/0000-0002-5779-9330)
- Haley Deamond (ORCID: https://orcid.org/0000-0002-2900-246X)
- Artur Kania (ORCID: https://orcid.org/0000-0002-5209-2520)
- Samantha Locke
- Kevin C. Lister (ORCID: https://orcid.org/0000-0001-7645-3928)
- Valerie Bourassa (ORCID: https://orcid.org/0000-0002-0689-2287)
- Philippe Séguéla (ORCID: https://orcid.org/0000-0001-7537-4427)
- Manon St-Louis
- Alfredo Ribeiro‐da‐Silva (ORCID: https://orcid.org/0000-0002-4125-0255)
- Rosana Rodrigues (ORCID: https://orcid.org/0000-0002-8180-7265)
- Behrang Sharif (ORCID: https://orcid.org/0000-0002-6451-2596)
- Marie-Ève Paquet (ORCID: https://orcid.org/0000-0001-6982-4970)
- Yaisa Andrews‐Zwilling
- Michael C. Carroll (ORCID: https://orcid.org/0000-0002-3213-4295)
- Farin B. Bourojeni (ORCID: https://orcid.org/0000-0002-0967-770X)
- Noosha Yousefpour (ORCID: https://orcid.org/0000-0001-6787-1781)
- Marc Parisien (ORCID: https://orcid.org/0000-0003-2924-5960)
- Jean S. Austin
- Chengyang Wang (ORCID: https://orcid.org/0000-0002-3739-5611)
- Nia Rahman-Khan Arana
Institutions
- Boston Children's Hospital (US)
- Montreal Neurological Institute and Hospital (CA)
- Harvard University (US)
- McGill University Health Centre (CA)
- Annexon Biosciences (United States) (US)
- Montreal Clinical Research Institute (CA)
- Université Laval (CA)
- McGill University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-17
- DOI
- https://doi.org/10.1038/s41467-025-59849-1
- Citations
- 22
- Primary Topic
- Pain Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 25.61
Funders
- Canadian Institutes of Health Research