Microglia Mediate Loss of Spinal Cord Inhibitory Synapses in Neuropathic Pain

Abstract

Spinal dorsal horn disinhibition has been implicated in neuropathic pain, a debilitating condition resulting from damage to the nervous system. Loss of dorsal horn inhibitory synapses has been proposed to contribute to the reduction of inhibitory tone in neuropathic pain. However, how nerve injury affects inhibitory synapses in relation to other synaptic populations and mechanisms mediating synaptic loss remain unknown. Using a nerve injury rodent model of neuropathic pain, we show that microglia selectively engulf synapses intrinsic to the dorsal horn, but not terminals of primary afferents. Furthermore, we reveal that microglia specifically remove complement-tagged inhibitory synapses that are presynaptic to dorsal horn interneurons and terminals of primary afferents. Inhibiting or depleting microglia prevented inhibitory synapse loss without affecting excitatory synapses and attenuated pain behaviour at chronic stages of neuropathic pain. These results define a new role for microglia in neuropathic pain pathogenesis: the selective pruning of spinal inhibitory synapses.

Keywords: Neuropathic Pain, spinal cord, Structural Plasticity, microglia, Synapse Pruning, Disinhibition