Department of Neurology and Neuroscience Program, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
J Neurosci. 2010 Feb 10;30(6):2051-9. doi: 10.1523/JNEUROSCI.5655-09.2010.
Dentate granule cell (DGC) neurogenesis persists throughout life in the hippocampal dentate gyrus. In rodent temporal lobe epilepsy models, status epilepticus (SE) stimulates neurogenesis, but many newborn DGCs integrate aberrantly and are hyperexcitable, whereas others may integrate normally and restore inhibition. The overall influence of altered neurogenesis on epileptogenesis is therefore unclear. To better understand the role DGC neurogenesis plays in seizure-induced plasticity, we injected retroviral (RV) reporters to label dividing DGC progenitors at specific times before or after SE, or used x-irradiation to suppress neurogenesis. RV injections 7 weeks before SE to mark DGCs that had matured by the time of SE labeled cells with normal placement and morphology 4 weeks after SE. RV injections 2 or 4 weeks before seizure induction to label cells still developing during SE revealed normally located DGCs exhibiting hilar basal dendrites and mossy fiber sprouting (MFS) when observed 4 weeks after SE. Cells labeled by injecting RV after SE displayed hilar basal dendrites and ectopic migration, but not sprouting, at 28 d after SE; when examined 10 weeks after SE, however, these cells showed robust MFS. Eliminating cohorts of newborn DGCs by focal brain irradiation at specific times before or after SE decreased MFS or hilar ectopic DGCs, supporting the RV labeling results. These findings indicate that developing DGCs exhibit maturation-dependent vulnerability to SE, indicating that abnormal DGC plasticity derives exclusively from aberrantly developing DGCs. Treatments that restore normal DGC development after epileptogenic insults may therefore ameliorate epileptogenic network dysfunction and associated morbidities.
齿状回颗粒细胞（DGC）神经发生在海马齿状回中终生存在。在啮齿动物颞叶癫痫模型中，癫痫持续状态（SE）刺激神经发生，但许多新生的 DGC 异常整合并且过度兴奋，而其他新生的 DGC 可能正常整合并恢复抑制。因此，改变的神经发生对癫痫发生的总体影响尚不清楚。为了更好地理解 DGC 神经发生在癫痫诱导可塑性中的作用，我们在 SE 之前或之后的特定时间注射逆转录病毒（RV）报告基因以标记正在分裂的 DGC 祖细胞，或使用 X 射线照射来抑制神经发生。在 SE 前 7 周注射 RV 以标记 SE 时已成熟的 DGC 标记 SE 后 4 周具有正常位置和形态的细胞。在癫痫发作诱导前 2 或 4 周注射 RV 以标记在 SE 期间仍在发育的细胞，在 SE 后 4 周观察时显示出正常位置的 DGC，具有 hilar 基底树突和苔藓纤维发芽（MFS）。在 SE 后注射 RV 标记的细胞在 SE 后 28 天显示 hilar 基底树突和异位迁移，但没有发芽；然而，在 SE 后 10 周检查时，这些细胞显示出强烈的 MFS。在 SE 之前或之后的特定时间通过脑局部照射消除新生 DGC 细胞群减少了 MFS 或 hilar 异位 DGC，支持 RV 标记结果。这些发现表明，发育中的 DGC 表现出对 SE 的成熟依赖性易感性，表明异常的 DGC 可塑性完全源自异常发育的 DGC。因此，在致痫性损伤后恢复正常 DGC 发育的治疗方法可能改善致痫性网络功能障碍和相关的发病率。
