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Janice R. Naegele




Temporal lobe epilepsy (TLE) is characterized by various neuropathological features including loss of hippocampal inhibitory interneurons and aberrant neurogenesis. A significant cell death is observed in the hilar region of the dentate gyrus. We used an interneuron transplantation approach to correct the underlying neural circuit defects in TLE and examine their ability to suppress spontaneous seizures. We used the pilocarpine model of TLE and transplanted inhibitory interneuron progenitors dissected from the medial ganglionic eminence (MGE) of embryonic day 13.5 mouse embryos. Long-term video EEG recordings showed that transplantation of inhibitory interneuron progenitors led to suppression of spontaneous seizures although the observed effects were not lasting. We further examined the synaptic integration and functioning of the transplanted interneurons. Using electrophysiological recordings in acute brain slices, we showed that transplanted interneurons form functional synapses onto the host neurons and increase synaptic inhibition onto the host granule cells (GCs). We further examined the ability of transplanted interneurons to synaptically innervated GCs generated in the epileptic brain. Using electrophysiology in combination with retroviral-labeling of adult-generated GCs, we showed that transplanted interneurons demonstrate remarkable plasticity and continue to form functional synapses onto GCs generated up to ten weeks after transplantation. Further analysis of the dendritic structure of these GCs showed that GCs innervated by the transplanted interneurons exhibited shorted total dendritic lengths as well as reduced Sholl intersections in the distal dendritic arbor. These findings provide evidence for the ability of transplanted interneurons to integrate into the host epileptic circuitry, induce morphological changes in the host neurons and lead to seizure suppression.

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