Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Molecular and Developmental Biology Program, University of Cincinnati, Cincinnati, Ohio 45237.
Department of Anesthesia, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio 45229.
eNeuro. 2016 Jan 9;2(6). doi: 10.1523/ENEURO.0087-15.2015. eCollection 2015 Nov-Dec.
Hippocampal dentate granule cells are among the few neuronal cell types generated throughout adult life in mammals. In the normal brain, new granule cells are generated from progenitors in the subgranular zone and integrate in a typical fashion. During the development of epilepsy, granule cell integration is profoundly altered. The new cells migrate to ectopic locations and develop misoriented "basal" dendrites. Although it has been established that these abnormal cells are newly generated, it is not known whether they arise ubiquitously throughout the progenitor cell pool or are derived from a smaller number of "bad actor" progenitors. To explore this question, we conducted a clonal analysis study in mice expressing the Brainbow fluorescent protein reporter construct in dentate granule cell progenitors. Mice were examined 2 months after pilocarpine-induced status epilepticus, a treatment that leads to the development of epilepsy. Brain sections were rendered translucent so that entire hippocampi could be reconstructed and all fluorescently labeled cells identified. Our findings reveal that a small number of progenitors produce the majority of ectopic cells following status epilepticus, indicating that either the affected progenitors or their local microenvironments have become pathological. By contrast, granule cells with "basal" dendrites were equally distributed among clonal groups. This indicates that these progenitors can produce normal cells and suggests that global factors sporadically disrupt the dendritic development of some new cells. Together, these findings strongly predict that distinct mechanisms regulate different aspects of granule cell pathology in epilepsy.
海马齿状颗粒细胞是哺乳动物成年期新生成的少数神经元细胞类型之一。在正常大脑中，新的颗粒细胞由颗粒下区的祖细胞生成，并以典型的方式整合。在癫痫的发展过程中，颗粒细胞的整合发生了深刻的改变。新细胞迁移到异位位置，并发育出定向错误的“基底”树突。尽管已经确定这些异常细胞是新生成的，但尚不清楚它们是否是由祖细胞池中的所有细胞普遍产生的，还是由少数“坏演员”祖细胞衍生而来的。为了探索这个问题，我们在表达 Brainbow 荧光蛋白报告基因构建体的小鼠中进行了克隆分析研究，这些小鼠在匹鲁卡品诱导的癫痫持续状态后 2 个月进行了检查，这种治疗会导致癫痫的发生。脑切片被制成半透明状，以便重建整个海马体并识别所有荧光标记的细胞。我们的研究结果表明，少数祖细胞在癫痫持续状态后产生了大部分异位细胞，这表明受影响的祖细胞或其局部微环境已经发生了病理变化。相比之下，具有“基底”树突的颗粒细胞在克隆群中分布均匀。这表明这些祖细胞可以产生正常细胞，并表明全局因素偶尔会破坏一些新细胞的树突发育。总的来说，这些发现强烈表明，不同的机制调节了癫痫中颗粒细胞病理的不同方面。
