Augmenting AMPA receptor signaling after spinal cord injury increases ependymal-derived neural stem/progenitor cell migration and promotes functional recovery

Abstract

Ependymal cells in the adult spinal cord become activated after spinal cord injury (SCI), gaining stem/progenitor cell properties. Although growing evidence has implicated these cells as potential players in the endogenous repair process after injury, their activation to a stem-cell-like state is transient and insufficient for adequate regeneration. Moreover, the drivers of their activation state remain largely unknown. Previous work suggested that AMPA receptors (AMPARs) regulate cultured ependymal-derived neural stem/progenitor cells (epNSPCs). In this study, we identified an AMPAR-dependent mechanism of epNSPC regulation after SCI. Using lineage tracing in adult mice, we demonstrate that conditional knockout of GluA1–GluA3 AMPAR subunits in epNSPCs abolishes glutamate-induced AMPA currents and impairs the acute activation of these cells after SCI. Augmenting AMPAR signaling with the ampakine CX546 alters the transcriptional profile of epNSPCs, maintaining their acute maturation reversal after SCI into the chronic injury period, increasing connexin-43 signaling, promoting their migratory capacity and enhancing ependymal–glial cell contacts, which may contribute to the spatial distribution and migratory pattern of ependymal cells after injury. CX546 treatment ameliorates the subacute decrease in corticospinal tract excitability after SCI and leads to long-term functional improvements. Together, this work identifies a neurotransmitter receptor-dependent mechanism of epNSPC activation after injury, which may be targeted to harness the regenerative potential of the spinal cord. Hachem et al. show that AMPAR signaling drives the acute activation of ependymal-derived neural stem/progenitor cells after spinal cord injury and that this mechanism can be targeted therapeutically to harness the endogenous regenerative potential of the spinal cord.