ErinElise Wilson

Introduction. Post-traumatic epilepsy (PTE) is one of the multiple comorbidities seen after traumatic brain injury (TBI) and accounts for up to 20% of all acquired epilepsies.^1-4 While the exact nature of pathogenic mechanisms is unclear, neurodegeneration yielding a hyperexcitable state accompanies the development of PTE after TBI.^1,2,5 Cells most vulnerable to degeneration following TBI are GABA-ergic interneurons with embryologic origins in the medial ganglionic eminence (MGE).⁶ Current PTE therapies are limited to antiepileptic drugs for seizure control.⁷ A recent study suggested a curative solution via transplantation of GABA-ergic precursor cells to alleviate hyperexcitability in the hippocampus and eliminate epileptic activity following TBI.⁸ Methods. Mice were subjected to controlled cortical impact to induce TBI. Next, a subgroup of TBI mice received MGE progenitor cell transplants harvested from GFP+ embryos. These grafts were injected 7 days post-TBI into CA1 and CA3 subfields of the hippocampus. The brain tissue samples were analyzed at 30 and 125 days following transplantation to assess graft cell survival, migration, and differentiation. Fresh hippocampal samples were analyzed for electrophysiologic properties of transplant-derived neurons at 45-60 days post-transplantation. Video-EEG recordings were performed beginning 5 months post-TBI to monitor ictal activity in three groups: TBI mice, TBI mice that received grafts, and the uninjured control group. In transplanted animals, immunofluorescence methods were used to identify the presence of GFP+, transplant-derived inhibitory GABA-ergic interneurons in the hippocampus. Results. Grafted interneuron precursors survived and migrated into injured areas of the hippocampus. The mature GFP+ cells displayed markers consistent with subclasses of GABA-ergic interneurons expressing somatostatin, parvalbumin, and neuronal nitric oxide synthase. Electrophysiologic studies identified fast-spiking, regular-spiking, and late-spiking interneurons among transplant-derived neurons, consistent with the properties of interneurons with MGE origins. Measurements of the inhibitory postsynaptic currents (IPSCs) in the dentate gyrus of graft recipients were similar to IPSCs in the control group. The majority of TBI mice that did not receive transplants exhibited ictal activity in the temporal lobe during the period of continuous EEG recordings. However, TBI mice receiving transplants did not display any seizure activity. Conclusion. The results indicate that grafted inhibitory interneuron precursors integrate into the existing circuitry of the injured regions of the brain and restore inhibitory signals lost following injury-induced neurodegeneration. Additionally, the transplanted cells appeared to block the evolution of TBI into PTE, suggesting a curative approach for avoiding PTE after TBI.

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