Department of Histology and Neuroanatomy, Tokyo Medical University, Tokyo, Japan.
Institute for Advanced Bioscience Research, Hoshi University, Tokyo, Japan.
Hippocampus. 2020 Mar;30(3):250-262. doi: 10.1002/hipo.23153. Epub 2019 Sep 5.
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.
在成年小鼠海马体中，新神经元由颗粒下层的放射状胶质样（RGL）神经干细胞产生，这些细胞向分子层延伸其顶端突起，并表达星形胶质细胞标志物胶质纤维酸性蛋白，但不表达星形胶质细胞标志物 S100β。在癫痫的啮齿动物模型中，据报道急性和轻度癫痫发作后成年海马体神经发生增加，但慢性和严重癫痫发作后减少。在本研究中，我们使用一种改良的匹罗卡品小鼠模型来研究癫痫急性发作阶段癫痫发作的严重程度如何影响神经发生和 RGL 神经干细胞，该模型通过维持体温来防止匹罗卡品引起的体温过低，从而导致癫痫发作的发生率高和死亡率低。在未发生癫痫持续状态（SE）的癫痫发作小鼠中，增殖祖细胞和未成熟神经元的数量显著增加，而 RGL 细胞没有变化。在发生 SE 的癫痫发作小鼠中，增殖祖细胞和未成熟神经元的数量不变，但具有顶端突起的 RGL 细胞数量显著减少。此外，大多数 RGL 细胞的突起向相反方向延伸至门区，约一半的异常 RGL 细胞表达 S100β。这些结果表明 SE 引起的癫痫发作导致 RGL 神经干细胞极性和性质发生变化，可能使其向星形胶质细胞分化，导致产生新颗粒细胞的神经干细胞减少。这也表明 RGL 干细胞的细胞极性对于维持成年神经干细胞的干细胞特性是重要的。
