Antagonists to excitatory amino acid (EAA) receptors can reduce the extent of chronic histopathology and functional deficits after experimental contusive spinal cord injury. Thus, EAA receptors affect outcome after spinal cord injury. Preliminary evidence now leads to the hypothesis that contusive injury alters EAA receptors in the spinal cord. Receptor subunit expression levels are affected acutely at 1 day and chronically at 1 month after injury. We propose that alterations in expression of specific subunits: (1) result in an altered composition of EAA receptor complexes in neurons and glia in the injured spinal cord: (2) contribute to cell death that occurs in the first 24 h after injury; (3) are triggered, at least in part, by the injury-induced release of EAA; and (4) that some of the acute alterations persist to produce a chronic plasticity of EAA receptors at one month after SCI. We will use a well- characterized rat model of spinal cord contusion to test these hypotheses. We will focus on injury-induced alterations in the GluR2 subunit which regulates the calcium permeability of alpha- amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and the NR2 subunits which strongly modulate function of N-methyl-D-aspartate (NMDA) receptors. Immunoprecipitation studies will be used to probe the subunit composition and tyrosine phosphorylation status of assembled receptor complexes at 24 hours and 1 month after injury. In situ hybridization and immuno- histochemistry will be used to characterize the temporal development of a specific subunit alteration in particular populations of neurons and glia to determine is correlation with cell death during the first 24 hours after injury. We will also investigate the extent to which the changes in receptor subunit composition can be pharmacologically mimicked with receptor agonists and/or blocked with antagonists. EAA receptors play a critical role in the function of normal spinal cord and are involved in secondary injury after spinal trauma. Further, NMDA and AMPA antagonists are putative therapeutic agents for individuals with acute SCI. Thus, understanding injury-induced alterations in spinal cord EAA receptors has important pathobiological and clinical implications.
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