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<p>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.</p>

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Targeting C1q prevents microglia-mediated synaptic removal in neuropathic pain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月17日

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  • 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 De Koninck,
  • Luda Diatchenko,
  • Arkady Khoutorsky,
  • Alfredo Ribeiro-da-Silva

摘要

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.