The polarity and properties of radial glia‐like neural stem cells are altered by seizures with status epilepticus: Study using an improved mouse pilocarpine model of epilepsy

Abstract

In the adult mouse hippocampus, new neurons are produced by radial glia‐like (RGL) neural stem cells in the subgranular zone, which extend their apical processes toward the molecular layer, and express the astrocyte marker glial fibrillary acidic protein, but not the astrocyte marker S100β. In rodent models of epilepsy, adult hippocampal neurogenesis was reported to be increased after acute and mild seizures, but to be decreased by chronic and severe epilepsy. In the present study, we investigated how the severity of seizures affects neurogenesis and RGL neural stem cells in acute stages of epilepsy, using an improved mouse pilocarpine model in which pilocarpine‐induced hypothermia was prevented by maintaining body temperature, resulting in a high incidence rate of epileptic seizures and low rate of mortality. In mice that experienced seizures without status epilepticus (SE), the number of proliferating progenitors and immature neurons were significantly increased, whereas no changes were observed in RGL cells. In mice that experienced seizures with SE, the number of proliferating progenitors and immature neurons were unchanged, but the number of RGL cells with an apical process was significantly reduced. Furthermore, the processes of the majority of RGL cells extended inversely toward the hilus, and about half of the aberrant RGL cells expressed S100β. These results suggest that seizures with SE lead to changes in the polarity and properties of RGL neural stem cells, which may direct them toward astrocyte differentiation, resulting in the reduction of neural stem cells producing new granule cells. This also suggests the possibility that cell polarity of RGL stem cells is important for maintaining the stemness of adult neural stem cells.

Hippocampal Transplants of Fetal GABAergic Progenitors Regulate Adult Neurogenesis in Mice with Temporal Lobe Epilepsy

“…4A-C). Comparison of sham operates of naïve and epileptic mice showed that Type 1 progenitors were significantly reduced in mice with SE, consistent with prior studies (Singh et al, 2015; Sasaki-Takahashi et al, 2020); GABA progenitor transplantation did not rescue Type 1 progenitors (Fig. 4D).…”

“…While additional studies are necessary to determine the precise molecular and cellular mechanisms for increasing survival and normalizing the direction of migration of adult-born GCs in TLE mice with GABAergic transplants, our findings suggest that the exogenous GABAergic cells may provide the signals for these phenomena. In agreement with prior studies, we found that mice with pilocarpine-induced epilepsy had reduced numbers of normal Type 1 progenitors with radial processes into the GCL (Sierra et al, 2015;Singh et al, 2015;Sasaki-Takahashi et al, 2020) but increased inverted Type 1 progenitors.…”

“…In epilepsy, inversion of the radial glial progenitors may be associated with ectopic migration of adult-born GCs, as the Type 1 cells may adopt an inverted morphology (Fig. 4B), with processes extending toward the hilus (Sasaki-Takahashi et al, 2020). Given our prior results showing many ectopic DCX + cells in SE mice, we next quantified abnormal GFAP + /SOX2 + Type 1 progenitors in the SGZ with inverted processes that extended into the hilus.…”

“…While the prevalence of Type 1 cells with radial processes did not appear to be altered following GABAergic progenitor transplantation, inverted Type 1 progenitors were markedly reduced following transplantation. Inversion of Type 1 progenitor processes can occur due to re-orientation of the centrosome away from the GCL toward the hilus, and centrosomal reorientation can be induced by seizures (Sasaki-Takahashi et al, 2020). This change in orientation of Type 1 progenitors might be regulated by reelin, which modulates neuronal migration (Zhao et al, 2004).…”

“…RGL cell polarity is altered by chronic TLE, assuming an inverted morphology, with radial processes directed toward the hilus of the dentate gyrus. This change in polarity may direct some RGL cells to transdifferentiate into astrocytes, suggesting a reduction in the neural stem cell pool that produces new GCs (Sasaki-Takahashi et al, 2020). A subset of GCs born after TLE induction in rodents develop abnormal structure, position, and orientation (Scharfman et al, 2007; Shapiro et al, 2008; Murphy et al, 2012).…”