CIRCUIT MECHANISMS OF SEIZURES IN THE PILOCARPINE MODEL OF CHRONIC EPILEPSY - CELL LOSS AND MOSSY FIBER SPROUTING

We used the pilocarpine model of chronic spontaneous recurrent seizure s to evaluate the time course of supragranular dentate sprouting and t o assess the relation between several changes that occur in epileptic tissue with different behavioral manifestations of this experimental m odel of temporal lobe epilepsy. Pilocarpine-induced status epilepticus (SE) invariably led to cell loss in the hilus of the dentate gyrus (D G) and to spontaneous recurrent seizures. Cell loss was often also not ed in the DG and in hippocampal subfields CA1 and CA3. The seizures be gan to appear at a mean of 15 days after SE induction (silent period), recurred at variable frequencies for each animal, and lasted for as l ong as the animals were allowed to survive (325 days). The granule cel l layer of the DG was dispersed in epileptic animals, and neo-Timm sta ins showed supra- and intragranular messy fiber sprouting. Supragranul ar messy fiber sprouting and dentate granule cell dispersion began to appear early after SE (as early as 4 and 9 days, respectively) and rea ched a plateau by 100 days. Animals with a greater degree of cell loss in hippocampal field CA3 showed later onset of chronic epilepsy (r = 0.83, p < 0.0005), suggesting that CA3 represents one of the routes fo r seizure spread. These results demonstrate that the pilocarpine model of chronic seizures replicates several of the features of human tempo ral lobe epilepsy (hippocampal cell loss, supra- and intragranular mes sy fiber sprouting, dentate granule cell dispersion, spontaneous recur rent seizures) and that it may be a useful model for studying this hum an condition. The results also suggest that even though a certain amou nt of cell loss in specific areas may be essential for chronic seizure s to occur, excessive cell loss may hinder epileptogenesis.