More than a million people suffer traumatic brain injury in the US every year, and among young adults head injury is the leading cause of death and disability. Of head injury survivors, 5% develop post-traumatic epilepsy, and following penetrating head injuries this number increases to 53%, presenting an enormous social and medical problem. However, the mechanisms by which head injury gives rise to epilepsy are poorly understood. The dentate gyrus of the hippocampal formation plays a central role in the regulation of excitability in the epilepsy-prone cortico-limbic system. The excitability of dentate granule cells, the principal output neurons of the dentate gyrus, is controlled by inhibitory cells called interneurons and excitatory cells named mossy hilar cells. In the previous funding period of this grant, we showed that surviving mossy cells play a crucial role in post-traumatic hyperexcitability in the dentate gyrus. Here we propose to test hypothesis that in the post-traumatic dentate gyrus a compromised dendritic inhibition to both granule cells and mossy cells constitutes a key mechanism underlying trauma-induced hyperexcitability. The hypothesis will be tested using the lateral fluid percussion model of head trauma in rodents, and the assessment will be carried out with electrophysiological and immunocytochemical methods at various time points after injury, complemented by biophysically realistic, large-scale computational modeling approaches. Our preliminary data indicate that head injury persistently modifies the dendritic excitability of mossy hilar cells and the feed-forward and feedback dendritic inhibition of granule cells in the dentate gyrus. The experiments of this proposal are designed to specifically target cellular-synaptic mechanisms underlying trauma-induced hyperexcitability. It is anticipated that defining the functional effects of head trauma on neurons, especially those in epilepsy-prone brain regions such as the hippocampal formation, will help the future development of novel anti-epileptic treatment strategies.
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