Balancing Neuroprotection with Functional Recovery: The Potential Role of the PNN in Preventing Excitotoxicity after SCI

Abstract

In spinal cord injury (SCI), initial mechanical trauma causes debilitating primary damage to neural cells and blood vessels. Following this, secondary cascades of downstream events occur, including inflammation, ischemia, and excitotoxicity — an increase in intracellular Ca2+ concentration from overactive glutamate (Glu) receptors leading to cell death. Additionally, there is an upregulation of the perineuronal net (PNN), a lattice‐like structure of the extracellular matrix (ECM) which modulates neural communication and homeostasis. The PNN is partially composed of negatively charged chondroitin sulfate proteoglycans (CSPGs). While CSPGs can stabilize plasticity and neuronal growth during development, these molecules become inhibitory to regeneration, sprouting and plasticity after injury, as well as contribute greatly to the glial scar. However, administration of the bacterial enzyme chondroitinase ABC (ChABC) can digest the PNN and CSPGs, ultimately promoting functional recovery. What remains unknown are the other impacts of removing the PNN at very acute stages of injury. We hypothesize that the PNN and its negatively charged CSPGs are upregulated after SCI as a neuroprotective response that attenuates excitotoxicity by acting as a buffer for Ca2+. To test our hypothesis, we induced excitotoxicity by injecting rats with a threshold dose of NMDA with or without ChABC utilizing the well defined spinal respiratory motor system. 59% of SCI occurs at the cervical level, and mechanical ventilation is the leading cause of death and restriction of independence in these cases. Therefore, we administered the dose instraspinally at the C4 level and paired treatment with intrapleural injection of cholera toxin‐B to retrogradely label the phrenic motor neuron pool, which innervates the diaphragm. Preliminary findings suggest that animals lacking the PNN have exacerbated cell death versus control. This implies that, following SCI, the body's main focus is to survive and not necessarily to preserve function. PNN upregulation after injury could be a conserved mechanism which promotes survival and CNS tissue preservation at the expense of plasticity and functional regeneration. The next steps are to detail the spread of ChABC and how long it takes for the PNN to regenerate. Future directions will investigate the optimal timing of ChABC administration to balance preserving cell survival with promoting functional recovery.Support or Funding InformationNINDS R01NS101105 (WJA)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.