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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037733-03
Application #
6393958
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Kleitman, Naomi
Project Start
1999-04-02
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$237,214
Indirect Cost
Name
Georgetown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Leung, Philberta Y; Wrathall, Jean R (2006) Local and distal responses to injury in the rapid functional recovery from spinal cord contusion in rat pups. Exp Neurol 202:225-37
Wrathall, Jean R; Emch, Gregory S (2006) Effect of injury severity on lower urinary tract function after experimental spinal cord injury. Prog Brain Res 152:117-34
Wu, Xiaofang; Yoo, Soonmoon; Wrathall, Jean R (2005) Real-time quantitative PCR analysis of temporal-spatial alterations in gene expression after spinal cord contusion. J Neurochem 93:943-52
Brown, Kwame M; Wolfe, Barry B; Wrathall, Jean R (2005) Rapid functional recovery after spinal cord injury in young rats. J Neurotrauma 22:559-74
Brown, Kwame M; Wrathall, Jean R; Yasuda, Robert P et al. (2004) Glutamate receptor subunit expression after spinal cord injury in young rats. Brain Res Dev Brain Res 152:61-8
Brown, Kwame M; Wrathall, Jean R; Yasuda, Robert P et al. (2002) Quantitative measurement of glutamate receptor subunit protein expression in the postnatal rat spinal cord. Brain Res Dev Brain Res 137:127-33
Pikov, Victor; Wrathall, Jean R (2002) Altered glutamate receptor function during recovery of bladder detrusor-external urethral sphincter coordination in a rat model of spinal cord injury. J Pharmacol Exp Ther 300:421-7
Pikov, V; Wrathall, J R (2001) Coordination of the bladder detrusor and the external urethral sphincter in a rat model of spinal cord injury: effect of injury severity. J Neurosci 21:559-69
Grossman, S D; Rosenberg, L J; Wrathall, J R (2001) Temporal-spatial pattern of acute neuronal and glial loss after spinal cord contusion. Exp Neurol 168:273-82
Grossman, S D; Rosenberg, L J; Wrathall, J R (2001) Relationship of altered glutamate receptor subunit mRNA expression to acute cell loss after spinal cord contusion. Exp Neurol 168:283-9

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