Department of Anesthesia and Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
J Neurosci. 2013 May 22;33(21):8926-36. doi: 10.1523/JNEUROSCI.5161-12.2013.
Accumulation of abnormally integrated, adult-born, hippocampal dentate granule cells (DGCs) is hypothesized to contribute to the development of temporal lobe epilepsy (TLE). DGCs have long been implicated in TLE, because they regulate excitatory signaling through the hippocampus and exhibit neuroplastic changes during epileptogenesis. Furthermore, DGCs are unusual in that they are continually generated throughout life, with aberrant integration of new cells underlying the majority of restructuring in the dentate during epileptogenesis. Although it is known that these abnormal networks promote abnormal neuronal firing and hyperexcitability, it has yet to be established whether they directly contribute to seizure generation. If abnormal DGCs do contribute, a reasonable prediction would be that the severity of epilepsy will be correlated with the number or load of abnormal DGCs. To test this prediction, we used a conditional, inducible transgenic mouse model to fate map adult-generated DGCs. Mossy cell loss, also implicated in epileptogenesis, was assessed as well. Transgenic mice rendered epileptic using the pilocarpine-status epilepticus model of epilepsy were monitored continuously by video/EEG for 4 weeks to determine seizure frequency and severity. Positive correlations were found between seizure frequency and (1) the percentage of hilar ectopic DGCs, (2) the amount of mossy fiber sprouting, and (3) the extent of mossy cell death. In addition, mossy fiber sprouting and mossy cell death were correlated with seizure severity. These studies provide correlative evidence in support of the hypothesis that abnormal DGCs contribute to the development of TLE and also support a role for mossy cell loss.
异常整合的成年海马齿状颗粒细胞（DGCs）的积累被假设为导致颞叶癫痫（TLE）的发展。DGCs 长期以来一直与 TLE 有关，因为它们通过海马调节兴奋性信号，并在癫痫发生期间表现出神经可塑性变化。此外，DGCs 异常，它们在整个生命中不断产生，新细胞的异常整合是癫痫发生期间齿状回大部分重构的基础。尽管已知这些异常网络促进异常神经元放电和过度兴奋，但尚未确定它们是否直接导致癫痫发作。如果异常的 DGCs 确实有贡献，那么一个合理的预测是，癫痫的严重程度将与异常 DGCs 的数量或负荷相关。为了验证这一预测，我们使用条件诱导的转基因小鼠模型来对成年产生的 DGCs 进行命运图谱分析。同样也评估了在癫痫发生中也涉及的苔藓细胞损失。使用匹罗卡品癫痫持续状态模型使转基因小鼠发生癫痫，然后通过视频/EEG 连续监测 4 周，以确定癫痫发作的频率和严重程度。发现癫痫发作的频率与（1）海马旁异位 DGCs 的百分比、（2）苔藓纤维发芽的量和（3）苔藓细胞死亡的程度呈正相关。此外，苔藓纤维发芽和苔藓细胞死亡与癫痫发作的严重程度相关。这些研究提供了相关证据支持异常 DGCs 有助于 TLE 的发展的假说，并支持苔藓细胞丢失的作用。
