The Developmental Stage of Dentate Granule Cells Dictates Their Contribution to Seizure-Induced Plasticity
The Developmental Stage of Dentate Granule Cells Dictates Their Contribution to Seizure-Induced Plasticity
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DOI：
10.1523/jneurosci.5655-09.2010
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发表时间：
2010-02-10
影响因子：
5.3
通讯作者：
Parent, Jack M.
中科院分区：
文献类型：
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作者：
Kron, Michelle M.;Zhang, Helen;Parent, Jack M.
齿状颗粒细胞（DGC）在海马齿状回的神经发生持续一生。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DGCs整合异常且过度兴奋，而其他DGCs可能整合正常并恢复抑制。因此，改变的神经发生对癫痫发生的总体影响尚不清楚。为了更好地了解DGC神经发生在癫痫诱导的可塑性中的作用，我们在SE之前或之后的特定时间注射逆转录病毒（RV）报告基因来标记分裂的DGC祖细胞，或者使用x射线照射来抑制神经发生。在SE前7周注射RV，以标记SE后4周放置和形态正常的标记细胞时成熟的DGCs。在癫痫发作诱导前2或4周注射RV以标记SE期间仍在发育的细胞，结果显示，SE后4周观察到的正常位置的DGCs表现出门脉基突和苔藓纤维发芽（MFS）。经SE后注射RV标记的细胞在SE后28 d显示出肝门基底树突和异位迁移，但未发芽；然而，在SE后10周检查时，这些细胞显示出强劲的MFS。在SE之前或之后的特定时间通过局灶脑照射消除新生儿DGCs队列，减少MFS或门静脉异位DGCs，支持RV标记结果。这些发现表明，发育中的DGCs对SE表现出成熟依赖的脆弱性，表明异常的DGCs可塑性完全来自异常发育的DGCs。因此，恢复癫痫性损伤后DGC正常发育的治疗可能会改善癫痫性网络功能障碍和相关发病率。
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.