In normal conditions, a vast majority of newly born neurons in the SGZ migrates into the GCL. However, in conditions such as SE, a large number of newly born neurons (i.e., granule cells) migrate away from the GCL into the dentate hilus ([45, 48, 57, , , , , –63]; Figure 1). An elegant study by Parent and associates  reports appearance of chain-like progenitor cell formations extending into the hilus and molecular layer after the SE, suggesting that seizures alter migratory behavior of dentate granule cell precursors. Likewise, ectopic dentate granule cells were also found in the hilus and molecular layer of epileptic human DG . Interestingly, ectopic granule cells in the dentate hilus exhibit several features of normal granule cells in the GCL, which comprise outgrowth of mossy fiber axons and incorporation of these axons into the pre-existing hippocampal circuitry [57, 60, 64] and standard granule cell membrane properties and firing behavior . Nevertheless, extensive studies by Scharfman and colleagues have shown that ectopic granule cells exhibit some features that are inconsistent with normal granule cells in the GCL. These include an increased proportion of somatic and dendritic asymmetric (presumably excitatory) synapses, enhanced mossy fiber innervation, a distinct pattern of activation during spontaneous seizures, and the occurrence of spontaneous epileptiform bursts [57, 60, 64, –66]. Recently, McCloskey and colleagues , by quantifying the population of ectopic granule cells at different times after pilocarpine-induced SE using immunostaining for Prox-1 (a marker of dentate granule cells ), demonstrated that the size of the hilar ectopic granule cell population after SE is substantial and stable over time. Additionally, correlation was found between the size of ectopic granule cell population and the frequency of behavioral seizures.
Thus, it appears that newly born granule cells that migrate into the hilus after the SE contribute to the development of chronic epilepsy. From this perspective, blocking the generation of ectopic granule cells following SE might be useful for thwarting the progression of SE into chronic epilepsy. Indeed, a study has tried to suppress the SE induced NSC proliferation in the DG with the antimitotic agent cytosine-β-d-arabinofuranoside (Ara-C) and evaluated the frequency of SRMS . In this study, rats received continuous intracerebroventricular infusions of Ara-C or vehicle for 14 days from one day before the onset of SE. Rats were video monitored for ∼12 hours per day from day 28 to day 34 after the SE. During this period, SRMS were observed in a majority of both vehicle-treated and Ara-C-treated rats; however, there was ∼70% reduction in the frequency of SRMS and ∼34% decrease in the duration of individual seizures in the Ara-C group. Interestingly, milder chronic epilepsy in Ara-C treated rats was associated with reduced density of ectopic granule cells in the hilus; however, the aberrant mossy fiber sprouting was unaffected . These results support the idea that newly born granule cells that migrate into the hilus shortly after the SE contribute to the development of chronic epilepsy. However, there are some concerns. First, as analyses of SRMS were done very early (28–34 days) after the SE, it is unknown whether beneficial effects of Ara-C would persist at later time points after the SE. Because in animal models of epilepsy SRMS are generally very robust at 2–4 months post-SE , it is necessary to analyze the effects of Ara-C exposure during the early post-SE period on SRMS occurring at extended time points after the SE in future studies. Second, examining seizure frequency or duration in the pilocarpine model as an endpoint is difficult because these animals show rather diffuse damage and the SRMS may not arise from the hippocampus. Third, it is not clear whether the positive effects of Ara-C exposure are a result of decreased number of ectopic granule cells or decreased proliferation of glia after the SE. Fourth, it is unknown whether Ara-C treatment would block other epileptogenic changes that promote the development of chronic seizures. Fifth, Ara-C treatment may also suppress the compensatory neurogenesis in the GCL that might otherwise improve inhibition . Thus, it remains to be seen whether complete elimination of aberrant neurogenesis after the SE would prevent the evolution of SE into chronic epilepsy.