More than 50,000 deaths are directly attributable to traumatic brain injury (TBI) annually in the U.S., while 80,000 TBI survivors exhibit significant neurologic sequelae. Even relatively minor TBI may lead to persistent negative consequences on functional performance. More serious disorders of higher cognitive function (e.g., intellectual and memory impairment, emotional lability, and decreased concentration) commonly result from TBI. In the brain, the hippocampus, which plays a critical role in memory formation, demonstrates frequent vulnerability to TBI. Interestingly, these impairments may also occur with minimal or absence of focal neurological deficit. TBI is most common in the 15-35 year age group, and significant financial ramifications are associated with the short and long term care of these patients. Using a mouse model, the proposed research will investigate the electrophysiological, anatomical and molecular alterations of the limbic hippocampus following TBI. Fluid percussion injury (FPI), through induction of hippocampus-dependent cognitive impairment, is a clinically relevant and highly reliable modality for mimicking TBI. The central hypothesis of this project contends that TBI induced cognitive deficits are explicable, in part, by pathological alterations in GABAergic function that precipitate regional imbalances between excitatory and inhibitory synaptic transmission, thereby causing hippocampal dysfunction. To test this hypothesis, we will undertake a detailed temporal and spatial determination and characterization of the anatomical and physiological alterations in GABAA-mediated synaptic function in the hippocampus of one week post- FPI and sham animals. Alterations in synaptic transmission will be assessed using patch clamp and extracellular field recording techniques. Neuronal loss will be determined by design-based stereological methodology, while changes in proteins mediating GABA metabolism will be examined using immunohistochemical and biochemical procedures. Such a multifaceted approach will not only increase the probability of identifying the specific injury-induced alterations in neuronal function, but may also elucidate the underlying molecular mechanisms associated with the traumatically injured brain. Understanding both the functional and molecular nature of these changes is necessary to potentiate the development of innovative therapies to possibly alleviate this devastating condition. ? ?
