Aberrant seizure‐induced neurogenesis in experimental temporal lobe epilepsy

Abstract

Neurogenesis in the hippocampal dentate gyrus persists throughout life and is increased by seizures. The dentate granule cell (DGC) layer is often abnormal in human and experimental temporal lobe epilepsy, with dispersion of the layer and the appearance of ectopic granule neurons in the hilus. We tested the hypothesis that these abnormalities result from aberrant DGC neurogenesis after seizure-induced injury. Bromodeoxyuridine labeling, in situ hybridization, and immunohistochemistry were used to identify proliferating progenitors and mature DGCs in the adult rat pilocarpine temporal lobe epilepsy model. We also examined dentate gyri from epileptic human hippocampal surgical specimens. Prox-1 immunohistochemistry and pulse-chase bromodeoxyuridine labeling showed that progenitors migrate aberrantly to the hilus and molecular layer after prolonged seizures and differentiate into ectopic DGCs in rat. Neuroblast marker expression indicated the delayed appearance of chainlike progenitor cell formations extending into the hilus and molecular layer, suggesting that seizures alter migratory behavior of DGC precursors. Ectopic putative DGCs also were found in the hilus and molecular layer of epileptic human dentate gyrus. These findings indicate that seizure-induced abnormalities of neuroblast migration lead to abnormal integration of newborn DGCs in the epileptic adult hippocampus, and implicate aberrant neurogenesis in the development or progression of recurrent seizures.

Localized delivery of fibroblast growth factor–2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model

“…As stated above, this migration is partly aberrant after SE, because many SGZ progenitors do not head toward the granular layer but toward the hilus (19). Therefore, we also analyzed DCX-positive cells.…”

“…In the adult hippocampus, neural progenitors are found both in the subgranular zone (SGZ) and in the caudal subventricular zone (SVZ). SE has been reported to increase proliferation of hippocampal progenitors in both areas, but SGZ progenitors differentiate into neurons that, in large part, migrate ectopically to the hilus and SVZ progenitors differentiate into glial, not neuronal, cells: that is, SE-induced neurogenesis is aberrant and may contribute to epileptogenesis (19,20).…”

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

“…For example, both ischemia and status epilepticus (SE) induce a transient increase in the rate of SGZ neurogenesis (Liu et al, 1998;Parent et al, 1997). Although this increase in neurogenesis has been suggested to contribute to aberrant hippocampal physiology (Parent et al, 1997(Parent et al, , 2006, the regenerative potential of adult progenitor cells make them attractive candidates for therapeutic interventions against neurodegenerative disorders. In line with this idea, the identification of the upstream neurotransmitter systems and intracellular signaling events that regulate the rate of injury-induced progenitor cell proliferation are of significant interest.…”

Compensatory Neurogenesis in the Injured Adult Brain

“…In normal animals, proliferating cells labeled with the mitotic marker bromodeoxyuridine (BrdU) are restricted to the SGZ of the hippocampus. In contrast, following seizure activity BrdU+ cells were found extensively in the dentate hilus and/or dentate molecular layer of the hippocampus, indicating aberrant migration of dividing cells in response to seizure-induced cell loss (Parent, et al, 1997, Scharfman, et al, 2000, Scharfman, et al, 2002, Parent, et al, 2006. Similarly, displaced granule cells have been observed in hippocampal tissues obtained from patients with TLE (Houser, 1990, Thom, et al, 2002, Liu, et al, 2008.…”