Abstracts

Rationale: Prolonged seizures are associated with hippocampal synaptic reorganization. "Mossy fiber sprouting" (MFS), the most striking example of this reorganization, involves the projection of dentate granule cell axons to new targets including the inner molecular layer (IML) where they appear to form recurrent excitatory synapses with their cells of origin. It has been postulated that this pathway may be involved in the development of spontaneous seizures following status epilepticus (SE) and other forms of hippocampal injury. In order to test this hypothesis, interventions that reduce the degree of MFS following SE need to be developed. By using a model of limbic SE that permits an uncoupling of anticonvulsant from neuroprotective properties, we examined the ability of drugs used in SE to reduce MFS. Methods: Limbic SE was induced in adult male Wistar rats via unilateral dorsal hippocampal electrical stimulation using a protocol permitting direct control over SE duration. After 140 minutes SE was terminated in all animals by stopping the stimulating current. Rats then received daily intraperitoneal injections of isotonic saline, fosphenytoin, valproic acid, lorazepam or pentobarbital for five days. After 30 days, 50 mm sections through the hippocampus were cut and processed for visualization of zinc-containing mossy fibers using the Timm silver-sulfide method. The degree of MFS in seven discrete portions of the dentate IML was estimated by measuring the density of silver reaction product in digitized, 8-bit greyscale images. Results: Animals subjected to 140 minutes of SE followed by isotonic saline injections had a moderate degree of MFS bilaterally. The heaviest MFS was seen at the crest and at the supra- and infrapyramidal ends of the IML. Treatment with fosphenytoin (10 mg/kg/day) was associated with a significant reduction in the degree of MFS bilaterally in these regions. The most striking reduction in MFS was seen at the crest where fosphenytoin treatment was associated with a 67% reduction in density. Discussion: These data suggest that fosphenytoin reduces MFS by a mechanism that may be unrelated to its anticonvulsant actions.