Time-dependent and selective microglia-mediated removal of spinal synapses in neuropathic pain
Noosha Yousefpour,
Samantha Locke,
Haley Deamond,
Chengyang Wang,
Lucas Marques,
Manon St-Louis,
Johanne Ouellette,
Arkady Khoutorsky,
Yves De Koninck,
Alfredo Ribeiro-da-Silva
Affiliations
Noosha Yousefpour
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC H3A 2B4, Canada
Samantha Locke
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC H3A 2B4, Canada
Haley Deamond
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC H3A 2B4, Canada
Chengyang Wang
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada
Lucas Marques
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada
Manon St-Louis
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada
Johanne Ouellette
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada
Arkady Khoutorsky
Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC H3A 2B4, Canada; Department of Anesthesia and Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montréal, QC H3G 1Y6, Canada
Yves De Koninck
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada; CERVO Brain Research Centre and Department of Psychiatry and Neuroscience, Université Laval, Québec, QC G1J 2G3, Canada
Alfredo Ribeiro-da-Silva
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC H3A 2B4, Canada; Corresponding author
Summary: Neuropathic pain is a debilitating condition resulting from damage to the nervous system. Imbalance of spinal excitation and inhibition has been proposed to contribute to neuropathic pain. However, the structural basis of this imbalance remains unknown. Using a preclinical model of neuropathic pain, we show that microglia selectively engulf spinal synapses that are formed by central neurons and spare those of peripheral sensory neurons. Furthermore, we reveal that removal of inhibitory and excitatory synapses exhibits distinct temporal patterns, in which microglia-mediated inhibitory synapse removal precedes excitatory synapse removal. We also find selective and gradual increase in complement depositions on dorsal horn synapses that corresponds to the temporal pattern of microglial synapse pruning activity and type-specific synapse loss. Together, these results define a specific role for microglia in the progression of neuropathic pain pathogenesis and implicate these immune cells in structural remodeling of dorsal horn circuitry.
