Investigating the mechanisms underlying cognitive impairments and seizure susceptibility following traumatic brain injury

Traumatic brain injury (TBI) is a significant health issue that often causes enduring cognitive deficits and decreased seizure threshold. The hippocampus, a structure crucial in higher cognitive function and seizure generation, is frequently damaged during TBI. To date TBI-induced pathology has been correlated with regional hippocampal cell loss. However, alterations in function do not always correlate with the degree of observed cell death. Alternatively, this thesis work is focused on the putative alterations of the surviving neurons following Fluid Percussion Injury (FPI), a clinically relevant model of TBI, in the mouse. Our findings suggest that FPI causes pathological alterations in hippocampal neurotransmission that regionally offset the existing delicate balance between excitatory and inhibitory systems necessary for hippocampal function.; Since long-term potentiation (LTP) is the leading cellular model thought to underlie learning and memory, experiments were undertaken to examine how injury affects area CA1 LTP. Brain slices derived from FPI animals demonstrated an inability to induce LTP, but not long-term depression (LTD), in area CA1 7 days post-injury. Our findings suggest that the potential mechanisms underlying the inability to induce and maintain area CA1 LTP are a result of injury causing: significantly smaller N-methyl-D-aspartate (NMDA) potentials, glutamate-induced excitatory currents, and evoked excitatory currents, increased dendritic spine size, and decreased expression of alpha-calcium calmodulin kinase II (alpha-CaMKII).; The dentate gryus is thought to function as a filter impeding excessive or aberrant activity from propagating further into the circuit and following experimental brain injury, this sub-region becomes more excitable. By investigating the components necessary for the efficacy of GABAA-mediated inhibition we found that protein and mRNA expression of the neuronal K-Cl co-transporter 2 (KCC2), which maintains the required low [Cl-]i, is reduced 7 days post-FPI. This causes a depolarizing shift in GABA A reversal potential, due to impaired chloride clearance, possibly resulting in reduced inhibitory efficiency.; These findings may underlie the injury-induced lack of area CA1 LTP and GABA efficacy and thus, contribute to cognitive impairments and seizures often associated with TBI. Furthermore, these results provide attractive sites for potential therapeutic intervention directed toward alleviating the devastating consequences of human TBI.