Microglial pruning of glycinergic synapses disinhibits spinal PKCγ interneurons to drive pain hypersensitivity in mice.
Journal:
Science translational medicine
Published Date:
Jun 18, 2025
Abstract
Microglial activation is linked to neuroinflammation in neuropathic pain. Recently, microglia-mediated synaptic pruning has received mounting attention. However, the exact role of spinal microglia in modulating neuropathic pain-associated neural circuits remains unclear. To investigate this question, we used pharmacological, optogenetic, and genetic manipulations combined with behavioral tests, confocal imaging, and patch-clamp studies in a murine spared nerve injury (SNI) model of neuropathic pain. We demonstrate that spinal microglia pruned inhibitory presynaptic terminals in SNI mice, contributing to the disinhibition of spinal protein kinase C γ (PKCγ) interneurons and facilitating neurotransmission from low-threshold Aβ fibers. Single-cell RNA sequencing revealed that SNI-associated microglial subpopulations exhibited high expression of liver X receptor, apolipoprotein E (), and complement C1q. Global knockout of , microglia-specific knockdown of , or treatment with anti-C1q monoclonal antibody reversed SNI-induced pruning of spinal inhibitory synapses, prevented the disinhibition of PKCγ interneurons, and reduced pain hypersensitivity. Our study suggests that destabilization of neural networks through microglia-mediated pruning of inhibitory synapses in the spinal cord contributes to the development of neuropathic pain in mice.
