Spinal cord injury (SCI) is a devastating syndrome, affecting approximately 250,000 people in the USA and costing 9.7 billion dollars annually. SCI is characterized by an acute loss of cells with the initial insult, followed by a secondary phase of cell death over several hours and days. Our long-term goal is to understand the mechanisms of this secondary cell death so that we can design drugs that spare tissue and improve function after SCI. The specific hypothesis is that the cytokine tumor necrosis factor alpha (TNFa) released after SCI facilitates excitotoxic cell death by enhancing membrane localization of AMPA receptors (AMPARs). This hypothesis is based on findings that 1) TNFa and glutamate levels rise after SCI; 2) TNFa enhances cell death caused by kainate (KA), an agonist of AMPARs; 3) TNFa causes trafficking of AMPA receptors to the cell membrane in vitro; 4) TNFa-induced AMPA receptor trafficking in vitro is selective for Ca++ permeable AMPARs.
The specific aims are to test: 1) whether SCI induces AMPA trafficking at time points when TNF levels are known to be elevated 2) whether TNFa nano-injection induces AMPAR trafficking in vivo. ? ? ?
