Background: The adult spinal cord contains a population of ependymal-derived neural stem/progenitor cells (epNSPCs) with the potential to enhance endogenous regeneration. However, little is known about the mechanisms that regulate the activation of these cells after injury. Recently, we discovered that glutamate excitotoxicity, a hallmark in the pathophysiology of acute SCI, promotes epNSPC proliferation/survival. Here, we characterize the downstream signaling pathways involved in this response and target this mechanism in vivo to enhance the endogenous regenerative capacity of these cells. Methods: epNSPCs were isolated from the central canal region of the adult spinal cord. In vitro pathway analysis was conducted using immunohistochemistry, RNAseq and Western Blot. In vivo, rats underwent SCI and at 1-week post-injury were randomized to receive CX546 (positive AMPAR modulator), or vehicle-control. Animals underwent behavioural testing and spinal cords were extracted for analysis. Results: Glutamate excitotoxicity leads to calcium influx in epNSPCs via AMPARs and together with Notch signaling drives proliferation and astrocytic differentiation. Positive modulation of AMPARs subacutely after SCI enhances epNSPC proliferation, astrogliogenesis, neurotrophin production, neuronal survival and functional recovery. Conclusions: We uncover an important mechanism by which AMPARs regulate the growth/phenotype of epNSPCs which can be targeted therapeutically to harness the regenerative potential of the injured spinal cord.