Traumatic Brain Injury and Post-traumatic Epilepsy Research Laboratory

Zakaria Mtchedlishvili, Ph.D.

The laboratory is dedicated to the study of the pathophysiological mechanisms by which traumatic brain injury (TBI) causes epilepsy. According to the Brain Trauma Foundation of America, at least 5.3 million Americans, or 2% of the U.S. population, currently live with disabilities resulting from TBI, and 1.5 million head injuries occur every year in the United States. Moderate and severe TBI is often followed by post-traumatic epilepsy (PTE). The latent period between the incident of TBI and the onset of seizures can take weeks, months, or even years. The main focus of my research is on the reorganization of GABAA receptor-mediated inhibitory neurotransmission and synaptic plasticity in the hippocampal dentate gyrus (DG) during the latent period following TBI, and strategies for potentiating diminished GABAA receptor-mediated transmission. Malfunction of GABAA receptor-mediated transmission in “epileptogenic” structures of brain is widely believed to be an underlying cause of epilepsy, and many antiepileptic drugs potentiate GABAergic transmission. GABAergic inhibition in the dentate gyrus is selectively vulnerable to head trauma. TBI induces loss of GABAergic interneurons in the hilus of the dentate gyrus, whereas glutamatergic DGCs are preserved. Small numbers of GABAergic interneurons inhibit thousands of DGCs and maintain homeostatic balance, or the “gate keeping” function of the dentate gyrus, which prevents the spread of glutamatergic excitation from the enthorinal cortex to the hippocampus. We are currently developing three separate research activities: 1) Allopregnanolone modulation of GABAA receptor-mediated inhibition in the DG after TBI. Allopregnanolone, a neurosteroid, is a powerful endogenous modulator of GABAA receptors, and its precursor progesterone has potent anti-inflammatory effect after head trauma.  My previous research has shown that allopregnanolone potentiation of GABAA receptors is severely diminished in epilepsy. 2) Determination of the effects of a broad-based chemokine inhibitor as a potent inhibitor of inflammatory cell recruitment following TBI and the subsequent development of PTE. 3) The potential of neural stem cells to compensate for cellular loss caused by TBI and to integrate within the existing neuronal network of the DG after injury. These studies will use cell-instructive polymeric microcapsules and genetically engineered neural stem cells in collaboration with a team of researchers from Carnegie Mellon University. Our studies will use combined electrophysiological, behavioral, neuroanatomical, immunocytochemical, and imaging approaches.

Supported by the Pennsylvania Department of Health #4100037701 (Health Research Formula Fund RFA)