DESCRIPTION: Two 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, 10 percent-15 percent develop post-traumatic epilepsy, and following penetrating head injuries this number increases to 53 percent, 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 inhibitory control of dentate granule cells, the principal output neurons of the dentate gyrus, is provided by local gamma-aminobutyric acid-releasing (GABAergic) interneurons. The goal of this study is to test the overall hypothesis that head injury results in a severe, long-lasting disturbance of the GABAergic control of dentate granule cells. The hypothesis will be tested using the lateral fluid percussion model of head trauma in rodents, and the assessment will be carried out with immunocytochemical and electrophysiological methods ar various time points after surgery. Our preliminary data indicate that head injury affects the survival of a crucially important GABAergic interneuronal class (the parvalbumin-immunoreactive basket and axo-axonic cells in the dentate hilus), which provide the perisomatic inhibitory control of granule cells. Furthermore, our data also indicate that head injury results in the appearance of novel GABAA receptor properties, and paradoxically increases the excitatory innervation of the surviving interneurons. 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.