Charles Tator Spinal Cord Injury Resident Research Award: Harnessing the Regenerative Potential of Endogenous Stem Cells After Spinal Cord Injury: A Novel Translationally Relevant Therapeutic Approach

Introduction: The adult spinal cord contains a population of endogenous ependymal-derived neural stem/progenitor cells (epNSPCs) that hold the potential to promote regeneration/repair after injury. epNSPCs are normally quiescent but are acutely activated after spinal cord injury (SCI). Despite this, the activation of these cells remains insufficient to promote robust neural regeneration/recovery. The drivers that activate epNSPCs remain unknown, and understanding the mechanisms that govern the biology of these cells is critical in developing a therapeutic strategy to harness their regenerative potential after injury. In this study, we define a novel mechanism of epNSPC activation, which can be targeted therapeutically to enhance recovery after SCI.

Methods: FoxJ1-CreER-tdTomato reporter mice were used for lineage tracing of epNSPCs. A conditional knock-out mouse line in which the AMPA-subtype glutamate receptor (AMPAR) is deleted in epNSPCs was generated to study the role of AMPARs in regulating epNSPCs. Mice underwent cervical compression-contusion SCI. To assess the effect of positive modulation of AMPARs, the clinically-relevant class of drugs known as ampakines was used. Mice (n=16/group) were randomized 1-week after SCI to receive the ampakine CX546 or vehicle control. Animals underwent electrophysiological testing, behavioural assessment and spinal cord extraction for histological/molecular analyses.

Results: Glutamate excitotoxicity, a hallmark in the pathogenesis of acute SCI, drives the activation of epNSPCs via AMPARs. Genetic knock-out of AMPARs in epNSPCs inhibits their activation following SCI. Positive pharmacological modulation of AMPARs after SCI enhances epNSPC proliferation and migration, increases neuronal survival, and improves long-term locomotor and forelimb function. On electrophysiological recordings, SCI decreases the excitability of corticospinal tract projections, which is improved with positive AMPAR modulation.

Conclusion : AMPARs regulate epNSPC activation and play a critical role in their response to SCI. Pharmacological targeting of this mechanism can be used to harness the regenerative potential of endogenous neural stem cells and improve motor recovery after SCI.