Abstracts

Rationale: Scarcity of inhibitory GABA-ergic interneurons in the hippocampus is one of the major pathological changes seen in chronic temporal lobe epilepsy (TLE). Hence, the idea of restraining spontaneous recurrent seizures (SRS) via grafting of cells that release GABA has received wide attention. Indeed, grafting of GABA-ergic cells into the epileptic foci has been shown to reduce SRS in several animal models. However, as patients with drug-resistant TLE are the most likely candidates for cell therapy (i.e. as an alternative to hippocampal resection surgery), it is vital that graft-efficacy studies be performed in prototypes where animals have experienced SRS for extended periods and also display co-morbidities of TLE such as cognitive and mood dysfunction at the time of grafting. Hence, this study examined the effects of grafting of GABA-ergic precursor cells into the hippocampi of F344 rats displaying chronic TLE typified by SRS, and memory and mood dysfunction.Methods: Freshly harvested GABA-ergic precursors derived from the medial ganglionic eminence (MGE) of embryonic day 14 rat brains were bilaterally transplanted into the hippocampus of a cohort of rats exhibiting chronic TLE. In order to simulate the scenario of grafting therapy for drug resistant TLE, grafting was performed to animals that experienced SRS for extended periods following an episode of status epilepticus (SE) induced through kainic acid. Another cohort of age-matched rats with chronic TLE and having similar extent of seizures was maintained as TLE only controls. Seizures in both groups were next measured through continuous video-electroencephalographic (EEG) recordings for two weeks. Animals were also tested behaviorally to determine the ability of grafts for easing memory and mood dysfunction. Results: Grafting reduced the frequency and time of behavioral SRS to 7-9% of pre-grafting scores. Frequencies of EEG-SRS with behavioral manifestation and all EEG-SRS were reduced to 3-13% of levels in TLE only controls, and stage V seizures were completely abolished. Times spent in EEG-SRS with behavioral manifestation and in all EEG-SRS were reduced to 1-7% of times in TLE only controls. Furthermore, grafting of GABA-ergic precursor cells improved spatial learning and reversed memory dysfunction in a water maze test. Grafting also ameliorated increased depression seen prior to grafting. Histological analyses revealed that ~30% of injected cells survived grafting, of which ~91% differentiated into GABA-ergic neurons with expression of markers of subclasses of GABA-ergic interneurons such as neuropeptide Y (10%), somatostatin (10%), parvalbumin (11%) calbindin (23%) and calretinin (16%). Conclusions: These results show that grafting of GABA-ergic precursor cells from the embryonic MGE into the hippocampus is a highly efficacious approach for diminishing the frequency and intensity of SRS, and reversing memory and mood dysfunction in chronic TLE.