Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainate-induced status epilepticus.

Abstract

Dentate granule cells are generally considered to be relatively resistant to excitotoxicity and have been associated with robust synaptogenesis after neuronal damage. Synaptic reorganization of dentate granule cell axons, the mossy fibers, has been suggested to be relevant for hyperexcitability in human temporal lobe epilepsy and animal models. A recent hypothesis suggested that mossy-fiber sprouting is dependent on newly formed dentate granule cells. However, we recently demonstrated that cycloheximide (CHX) can block the mossy-fiber sprouting that would otherwise be induced by different epileptogenic agents and does not interfere with epileptogenesis in those models. Here, we investigated cell damage and neurogenesis in the dentate gyrus of pilocarpine- or kainate-treated animals with or without coadministration of CHX. Dentate granule cells were highly vulnerable to pilocarpine induced-status epilepticus (SE), but were hardly damaged by kainate-induced SE. CHX pretreatment markedly reduced the number of injured neurons after pilocarpine-induced SE. Induction of SE dramatically increased the mitotic rate of KA- and KA + CHX-treated animals. Induction of SE in animals injected with pilocarpine alone led to 2-7-fold increases in the mitotic rate of dentate granule cells as compared to 5- and 30-fold increases for pilocarpine + CHX animals. We suggest that such increased mitotic rates might be associated with a protection of a vulnerable precursor cell population that would otherwise degenerate after pilocarpine-induced SE. We further suggest that mossy-fiber sprouting and neurogenesis of granule cells are not necessarily linked to one another.