Spinal cord trauma causes extended neurologic disability, with limited treatment options, and serious social and economic consequences. Both gray and white matter damage contribute to functional disability. While recent studies have begun to identify mechanisms contributing to neuronal injury, mechanisms underlying oligodendrocyte (oligo) or axonal injury remain unclear. Understanding the mechanisms of oligo death, and the subsequent consequences relative to neuronal and axonal injury and recovery, and behavioral outcome, could provide valuable clues to novel therapies for spinal cord injury and, possibly, other neurologic diseases such as stroke. The major objective of this proposal is to systematically study excitotoxic, AMPA receptor-mediated death of oligos in vitro and determine the relative role of this mechanism in spinal cord trauma. Extracellular glutamate is known to be elevated to high levels consequent to spinal cord trauma. Our preliminary evidence suggests that oligos express high levels of AMPA-type glutamate receptors, and can be destroyed by moderate overactivation of these AMPA receptors. Expression of functional AMPA-type glutamate receptors will be examined by western blots, immunohistochemistry, dye physiology, and electrophysiology in primary culture. The hypothesis that oligos in vitro and in vivo can be destroyed by toxic overactivation of AMPA receptors will be demonstrated pharmacologically by direct application of glutamate, and AMPA receptor specific agonists and antagonists in primary culture and in vivo spinal cord preparation. The nature of AMPA receptor-mediated oligo death, necrosis vs apoptosis, will be characterized in vitro by dy physiology, EM cellular morphology, and susceptibility in Bax knock-out and Bcl-2 over-expressing murine cultures. Finally, the hypothesis that blockade of AMPA receptor- mediated oligo death will reduce white matter damage in rat model of spinal cord trauma will be tested by selective application of AMPA receptor antagonists, and studying the possible relation of oligo death and neuronal injury. The effects of these manipulations on behavioral outcome from spinal cord trauma will be assessed. If our hypothesis correct, measures directed at reducing AMPA receptor-mediated oligo death may be useful in the acute treatment of spinal cord injury.
