NMDA Receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL Receptor-related Protein-1 (LRP1) to trigger cell-signaling in response to protein ligands in neurons. Herein, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells (SCs) and functions independently and with LRP1 to regulate SC physiology. The NR1 and NR2b NMDA-R subunits were expressed by cultured SCs and up-regulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 and promote SC migration required the NMDA-R. NR1 gene-silencing compromised SC survival. Injection of the LRP1 ligands, tissue-type plasminogen activator (tPA) or MMP9-PEX, into crush-injured sciatic nerves, activated ERK1/2 in SCs in vivo and the response was blocked by systemic treatment with the NMDA-R inhibitor, MK801. tPA was unique amongst the LRP1 ligands examined because tPA activated cell-signaling and promoted SC migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a SC signaling receptor for protein ligands and a major regulator of SC physiology, which may be particularly important in PNS injury
