NMDA receptor dysfunction after traumatic brain injury

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DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the number one cause of pediatric death and disability in the U.S. Pediatric TBI accounts for over 100,000 annual U.S. hospital admissions, and many more cases either are not admitted or do not come to medical attention. A significant number of head-injured children develop lasting behavioral or cognitive impairment. The underlying mechanism for these sequelae may be widespread neuronal dysfunction, rather than cell death. One likely mediator of these deficits is the N-methyl-D-aspartate receptor (NMDAR), whose activation is of vital importance for normal brain maturation and experience-dependent plasticity. NMDAR subunit composition is profoundly altered after developmental TBI (see Preliminary Study 2). Therefore, the following hypotheses are proposed: 1) Post-TBI changes in NMDAR structure composition will result in impaired NMDAR function and 2) Impaired NMDAR function following developmental TBI will result in anatomical changes in the mature brain. To address these hypotheses, NMDAR subunit changes will be regionally localized in the traumatically injured immature brain using molecular measures of gene and protein expression. NMDAR dysfunction will then be assessed directly in these regions, by measuring induction of long-term potentiation and NMDA-mediated calcium flux. Finally, investigations into late sequelae of traumatically induced NMDAR dysfunction will utilize a novel combination of developmental concussion followed by experience-dependent plasticity induced by rearing in an enriched environment (EE). After developmental TBI and EE rearing, lasting changes in molecular markers for dendrites and synapses, as well as structural alterations in the dendritic trees themselves, may be manifest in adulthood. This study will provide a different perspective on head injury by focusing on injury-induced neuronal dysfunction rather than cell death, in a setting of ongoing development where a temporary impairment can be translated into a permanent deficit.