Continuous Cytosine-β-D-arabinofuranoside Infusion Reduces Ectopic Granule Cells in Adult Rat Hippocampus with Attenuation of Spontaneous Recurrent Seizures Following Pilocarpine-induced Status Epilepticus Jung KH, Chu K, Kim M, Jeong SW, Song YM, Lee ST, Kim JY, Lee SK, Roh JK Eur J Neurosci 2004;19(12):3219–3226 Brief or prolonged seizures induce various patterns of plasticity. Axonal or dendritic remodeling and development of ectopic granule cells have been described in the hilus and molecular layer of the adult rodent hippocampus. Hippocampal cell proliferation also occurs after seizures. However, whether the seizure-induced cell proliferation plays a pathologic or reparative role in the epileptic brain is unknown. In this study, we attempted to suppress the seizure-induced cell proliferation with the antimitotic agent cytosine- β-D-arabinofuranoside (Ara-C) and to examine the development of spontaneous recurrent seizures (SRSs). Experimental status epilepticus was induced with pilocarpine, and Ara-C or vehicle alone was infused continuously with an osmotic minipump. SRSs were video-monitored. Bromodeoxyuridine (BrdU) immunohistochemistry was used for the spatial and temporal analysis of hippocampal cell proliferation, and double labeling with NeuN, calbindin, and glial fibrillary acidic protein (GFAP) antibodies was performed for the differentiation of BrdU-positive cells. Timm staining also was performed for evaluation of mossy-fiber sprouting (MFS). With continuous Ara-C infusion, the likelihood of developing SRSs was decreased, and during the latent period, the development of ectopic granule cells in the hilus and new glia in the CA1 area was reduced when compared with that in the vehicle-infused group, whereas MFS was not altered. The results suggest that the hippocampal cell proliferation plays a proepileptogenic role rather than a compensatory role, and that the epileptogenic process may be associated with the generation of new glia in the CA1 area or new neurons in the dentate gyrus, particularly the ectopically located hilar granule cells, or both. Increased Neurogenesis and the Ectopic Granule Cells after Intrahippocampal BDNF Infusion in Adult Rats Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S Exp Neurol 2005;192(2):348–356 Evidence suggests that brain-derived neurotrophic factor (BDNF) influences the birth of granule cells in the dentate gyrus, which is one of the few areas of the brain that demonstrates neurogenesis throughout life. However, studies to date have not examined this issue directly. To do so, we compared the effects of BDNF, phosphate-buffered saline (PBS), or bovine serum albumin (BSA) on neurogenesis after infusion into the hippocampus of the normal adult rat, by using osmotic pumps that were implanted unilaterally in the dorsal hilus. BDNF, PBS, and BSA were infused for 2 weeks. The mitotic marker BrdU was administered twice daily during the 2-week infusion period. At least 1 month after infusion ended, brains were processed immunocytochemically by using antibodies to BrdU, a neuronal nuclear protein (NeuN), or calbindin D28K (CaBP), which labels mature granule cells. Stereology was used to quantify BrdU-labeled cells in the dorsal hippocampus that were double-labeled with NeuN or CaBP. A statistically significant increase in BrdU+/NeuN+ double-labeled cells was noted in the granule cell layer after BDNF infusion, relative to that in controls. The values for BrdU+/NeuN+ cells were similar to those for BrdU+/CaBP+ cells, indicating that most new neurons were likely to be granule cells. In addition, BrdU+/NeuN+-labeled cells developed in the hilar region after BDNF infusion; these have previously been identified only after severe continuous seizures (status epilepticus) and associated pathologic changes. Remarkably, neurogenesis also was increased contralaterally, but BDNF did not appear to spread to the opposite hemisphere. Thus, infusion of BDNF to a local area can have widespread effects on hippocampal neurogenesis. The results demonstrate that BDNF administration to the dentate gyrus leads to increased neurogenesis of granule cells. They also show that ectopic granule cells develop after BDNF infusion, which suggests that ectopic migration is not necessarily confined to pathologic conditions. These results are discussed in light of the evidence that BDNF increases neuronal activity in hippocampus. Thus, the mechanisms underlying neurogenesis after BDNF infusion could be due to altered activity as well as to direct effects of BDNF itself, and this is relevant to studies of other growth factors because many of them have effects on neuronal excitability that are often not considered.
Morphological Alterations in Newly Born Dentate Gyrus Granule Cells That Emerge after Status Epilepticus Contribute to Make Them Less Excitable