"Epileptic" brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology.

Sustained electrical stimulation of the perforant path evokes granule cell population spikes and epileptiform discharges, abolishes recurrent inhibition in the granule cell layer and induces a reproducible pattern of hippocampal damage (see preceding paper, this volume, for electrophysiological and light microscopic findings). Electron microscopic findings described here reveal that the hippocampal damage is identical in pattern and cytopathological detail to that associated with sustained limbic seizures induced by chemical convulsants such as kainic acid, folic acid and dipiperidinoethane. Acutely swollen dendritic segments distributed in a laminar pattern corresponding closely with the termination of putative glutamate or aspartate-containing fibers, including those of the perforant path, were a conspicuous finding. Cell bodies of CA1 and CA3 pyramidal neurons and various interneurons in the hilus and elsewhere displayed degenerative changes ranging from mild to severe. Both the dendritic and somal degenerative changes closely resemble the "excitotoxic" type of damage that the putative transmitters glutamate and aspartate are known to cause. It is proposed, therefore, that sustained electrical stimulation of the perforant path results in excessive synaptic release and accumulation of glutamate (or aspartate) at numerous dendrosomal receptors in the hippocampus with consequent degeneration of the dendrosomal structures housing these receptors. Early excitotoxic effects on interneurons that mediate recurrent inhibition may play an important role in the observed loss of recurrent inhibition and in the evolution of subsequent excitotoxic degeneration in the hippocampus.