Abstracts

RATIONALE: In temporal lobe epilepsy, extensive synaptic reorganization in the hippocampal formation has been postulated to lead to recurrent seizures. To determine the factors contributing to the onset of seizures in the lithium-pilocarpine model, we investigated alterations of GABAergic circuits in the dentate gyrus. METHODS: Adult male rats were injected with lithium and pilocarpine and developed status epilepticus (SE). Four groups of rats were sacrificed at 24 h, 6 days, or 12 days after SE, and the last group after the onset of the first spontaneous recurrent seizures (SRS). Single and double-labeling immunohistochemistry was performed with antibodies to the calcium binding proteins calretinin (CR), parvalbumin (PV) and calbindin (CB), the neuronal GABA transporter GAT1 and the GABA synthesizing enzyme GAD. Cell counts were performed to quantify loss of interneurons (INs) and optical densities were measured for quantification of GABAergic terminals. The results were compared to vehicle-treated rats that did not undergo SE. RESULTS: A prominent sprouting of GABAegic terminals was observed after 6 days, 12 days and in the SRS group in the inner molecular layer of the dentate gyrus, evidenced by an increase of GAT1 staining, co-localized with GAD staining. The number of PV- and CR-positive INs was decreased in the hilus already at 24 h and there was no recovery thereafter. In contrast, the number of CB-positive INs did not decrease at any time. Rather, it was increased selectively in the hilus of SRS rats. These CB-INs were not seen in the other groups and had larger somas than control CB-INs. Their dendrites were more numerous and extended through the granule cell layer in the molecular layer. CONCLUSIONS: In the lithium-pilocarpine model, extensive reorganization of inhibitory circuits occurs in the dentate gyrus before the onset of SRS, as indicated by the sprouting of GAT1/GAD terminals and the partial loss of PV- and CR-positive INs. SRS appear selectively associated with increased CB expression in hilar interneurons. These alterations might be responsible for the synchronization of excitability, leading to seizures.