We used the pilocarpine model of chronic spontaneous recurrent seizures to evaluate the time course of supragranular dentate sprouting and to assess the relation between several changes that occur in epileptic tissue with different behavioral manifestations of this experimental model of temporal lobe epilepsy. Pilocarpine-induced status epilepticus (SE) invariably led to cell loss in the hilus of the dentate gyrus (DG) and to spontaneous recurrent seizures. Cell loss was often also noted in the DG and in hippocampal subfields CA1 and CA3. The seizures began to appear at a mean of 15 days after SE induction (silent period), recurred at variable frequencies for each animal, and lasted for as long as the animals were allowed to survive (325 days). The granule cell layer of the DG was dispersed in epileptic animals, and neo-Timm stains showed supra- and intragranular mossy fiber sprouting. Supragranular mossy fiber sprouting and dentate granule cell dispersion began to appear early after SE (as early as 4 and 9 days, respectively) and reached 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 for seizure spread. These results demonstrate that the pilocarpine model of chronic seizures replicates several of the features of human temporal lobe epilepsy (hippocampal cell loss, supra- and intragranular mossy fiber sprouting, dentate granule cell dispersion, spontaneous recurrent seizures) and that it may be a useful model for studying this human condition. The results also suggest that even though a certain amount of cell loss in specific areas may be essential for chronic seizures to occur, excessive cell loss may hinder epileptogenesis.
We have studied the distribution of gamma-aminobutyric acid (GABA) neurons, axons, and synapses in the rat and monkey hippocampal formation by using glutamate decarboxylase (GAD) immunocytochemistry together with Nissl stains, electron microscopy, and double-labeled retrograde transport of horseradish peroxidase. The numbers of GAD-containing (putative GABA) neurons and their percentages compared to all Nissl-stained neurons were calculated throughout all the various fields and strata of the mammalian hippocampus. Although their numbers are greatest in the polymorph region of the fascia dentata (FD) and in the principal cell layers stratum pyramidale (SP) and stratum granulosum (SG), GAD immunoreactive (GAD-IR) cells are numerous in other strata that contain mostly dendrites and scattered cells. These GAD-IR (putative GABA) neurons in dendritic regions may be involved in feedforward dendritic inhibition or may directly inhibit nearby neurons. We used a postmortem delay technique, which resulted in apparent diffusion of GAD into dendrites and axons and allowed better visualization of the extensive dendritic domain of GAD-IR neurons. Computerized image analysis of GAD-IR puncta indicated that putative GABA terminals were numerous on apical and basilar dendrites of all pyramidal cells but unexpectedly highest in the monkey presubiculum. In the rat, GAD-IR neurons projected axons ipsilaterally from every region to the fascia dentata and CA1; however, commissural GAD-IR axons to the fascia dentata arose from GAD-IR neurons in only the contralateral fascia dentata and subiculum. Electron microscopy of GAD-stained hippocampus identified GAD-IR neurons with non-GAD-IR (possibly excitatory) synapses and GAD-IR terminals on somata and dendrites, 80% being the symmetric type and 20% the asymmetric type. In contrast, non-GAD-IR terminals were asymmetric 80% of the time.
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