To Prune or to Protect: Complement-Mediated Microglial Synaptic Pruning as a Therapeutic Target in Neuropathic Pain

Neuropathic pain affects approximately 7-10% of the general population, yet available pharmacological treatments remain largely inadequate. Central sensitization in the spinal dorsal horn, partially driven by microglia-mediated synaptic remodeling, constitutes a core yet incompletely characterized mechanism underlying this disorder. Following peripheral nerve injury, spinal microglia engulf and eliminate dorsal horn synapses via a complement-dependent pathway reactivated from a developmental pruning program; this pathway exhibits preferential selectivity for inhibitory relative to excitatory synaptic subtypes. This process is positively regulated by the LXR-ApoE-C1q transcriptional axis, the Spi1-Clec7a axis, and an emerging phosphatidylserine-dependent "eat-me" signal, and is negatively modulated by the endogenous ganglioside GT1b. The selective elimination of glycinergic inputs onto PKCγ interneurons drives disinhibition of spinal nociceptive circuits, thereby contributing to the pathogenesis of mechanical allodynia. Pharmacological inhibition of C1q, microglia-specific ApoE knockdown, and intrathecal Spi1 silencing each attenuate pain hypersensitivity in preclinical rodent models, which have been conducted predominantly in male subjects. However, a causal link between structural synapse loss and specific pain phenotypes has been definitively established only for the PKCγ circuit. Furthermore, the generalizability of these findings to female animals, non-mechanical neuropathic pain subtypes, and human disease remains unvalidated. This review synthesizes current evidence on microglia-synapse interactions in neuropathic pain, applies an explicit levels-of-evidence framework to distinguish direct empirical findings from inferential conclusions, critically evaluates sex as a biological variable across this signaling pathway, delineates key translational gaps, and presents a mechanistic framework to guide the development of disease-modifying analgesic strategies targeting the microglia-synapse interface.