LAUSR

Peripheral inflammation overrides a developmental, ubiquitin-mediated switch limiting neuronal sensitivity. A painful return to developmental NMDAR activity Neuronal sensitivity is mediated, in part, by NMDA receptor (NMDAR) signaling, and increased abundance of GluN2B-containing NMDARs in sensory neuronal synapses is associated with enhanced nociception and pain. Using rodents, Zhang et al. found that GluN2B content in the sensory neurons of the spine is progressively restricted during early development and maintained at low abundance by the E3 ubiquitin ligase Cbl-b during adulthood. However, peripheral inflammation induced the dephosphorylation of Cbl-b and impaired its interaction with GluN2B, and the increase in GluN2B abundance enhanced NMDAR activity and neuronal sensitivity to touch. Identifying a way to target this mechanism might be therapeutic in patients suffering from inflammatory peripheral neuropathy. N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found that the E3 ubiquitin ligase Cbl-b was enriched in the spinal cord dorsal horn neurons of mice and rats and suppressed GluN2B abundance during development and inflammatory pain. Cbl-b abundance increased from postnatal day 1 (P1) to P14, a critical time period for synapse maturation. Through its N-terminal tyrosine kinase binding domain, Cbl-b interacted with GluN2B. Ubiquitination of GluN2B by Cbl-b decreased the synaptic transmission mediated by GluN2B-containing NMDARs. Knocking down Cbl-b in vivo during P1 to P14 led to sustained retention of GluN2B at dorsal horn synapses, suggesting that Cbl-b limits the synaptic abundance of GluN2B in adult mice. However, peripheral inflammation induced by intraplantar injection of complete Freund’s adjuvant resulted in the dephosphorylation of Cbl-b at Tyr363, which impaired its binding to and ubiquitylation of GluN2B, enabling the reappearance of GluN2B-containing NMDARs at synapses. Expression of a phosphomimic Cbl-b mutant in the dorsal horn suppressed both GluN2B-mediated synaptic currents and manifestations of pain induced by inflammation. The findings indicate a ubiquitin-mediated developmental switch in NMDAR subunit composition that is dysregulated by inflammation, which can enhance nociception.