RIN1 regulates developmental and pain-related plasticity in spinal synapses via NMDA receptor subunit trafficking

Neuronal activity and sensory experience regulate the subunit stoichiometry of synaptic N-methyl-D-aspartate subtype glutamate receptors (NMDARs), a critical determinant for brain development, synaptic plasticity, and a line of neurological disorders. Here we found that Ras and Rab interactor 1 (RIN1), a neuron-specific protein in the brain, played an important role in dictating synaptic NMDAR subunit composition in spinal cord somatostatin-positive (SOM+) neuron, a key component in the spinal circuit transmitting mechanical pain in mice. Our data showed that the protein level of RIN1 was low early after birth, which progressively increased with synapse maturation and promoted the switch from synaptic GluN2B- to GluN2A-containing NMDARs. In adult mice, the nerve injury-induced pathological pain paralleled a significant increase of RIN1 protein in spinal SOM+ neurons, which drove a new round of GluN2B-to-GluN2A switching at mature synapses. Our data revealed the molecular mechanisms by which RIN1 differentially regulated the synaptic trafficking of GluN2B and GluN2A receptors, and implied that RIN1-mediated pathological switch of NMDAR subunit composition strikingly altered the analgesic efficacy of distinct NMDAR subunit antagonists with the development of neuropathic pain.