Ferland R J, Gross R A, Applegate C D
Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Neuroscience. 2002;115(3):669-83. doi: 10.1016/s0306-4522(02)00514-6.
Repeated flurothyl-induced generalized forebrain seizures result in a progressive and permanent lowering of the generalized seizure threshold in mice and an increase in the percentage of animals expressing forebrain-brainstem seizures, when rechallenged with flurothyl, after a stimulation-free period. Since this seizure paradigm serves as an excellent model for examining changes in seizure threshold and seizure propagation, we were interested in examining mitotic activity in hippocampal progenitors following flurothyl-induced epileptogenesis. In the present studies, we investigated (1). the effect of one or eight flurothyl-induced seizures on mitotic activity in the hippocampal dentate gyrus of adult mice measured by 5-bromo-2'-deoxyuridine incorporation, (2). the time course of change in hippocampal mitotic activity, (3). the cellular phenotype of these mitotically active cells, and (4). the relationship of changes in mitotic activity to changes in seizure threshold and phenotype. Significant increases in hippocampal mitotic activity were observed in mice exposed to either one or eight flurothyl-induced seizures. Increases were observed at 1 and 3 days following one seizure, and at 0, 1, 3, and 7 days following eight seizures. Confocal analyses, using neuronal and glial markers, suggest that the majority of these mitotic cells are neurons. In addition, no correlation was observed between hippocampal mitotic activity and the final seizure type that animals expressed following incubation and flurothyl retest. A significant correlation was observed between hippocampal mitotic activity and seizure threshold in flurothyl-kindled mice. Overall, these results indicate that both one and eight flurothyl-induced seizures are potent inducers of hippocampal neurogenesis in adult mice. Results further suggest that the increases in hippocampal neurogenesis are not directly related to the processes that underlie the shift in behavioral seizure phenotype, but may be involved in either the establishment or the maintenance of seizure threshold in this flurothyl model of epileptogenesis.
反复给予氟烷诱导的全脑性癫痫发作会导致小鼠的全身性癫痫发作阈值逐渐永久性降低，并且在无刺激期后再次用氟烷激发时，表现出前脑 - 脑干癫痫发作的动物百分比增加。由于这种癫痫发作模式是研究癫痫发作阈值变化和癫痫发作传播的优秀模型，我们有兴趣研究氟烷诱导的癫痫发生后海马祖细胞的有丝分裂活性。在本研究中，我们调查了：（1）通过5-溴-2'-脱氧尿苷掺入法测量的一次或八次氟烷诱导的癫痫发作对成年小鼠海马齿状回有丝分裂活性的影响；（2）海马有丝分裂活性变化的时间进程；（3）这些有丝分裂活性细胞的细胞表型；（4）有丝分裂活性变化与癫痫发作阈值和表型变化之间的关系。在暴露于一次或八次氟烷诱导癫痫发作的小鼠中观察到海马有丝分裂活性显著增加。一次癫痫发作后1天和3天观察到增加，八次癫痫发作后0天、1天、3天和7天观察到增加。使用神经元和神经胶质标记物的共聚焦分析表明，这些有丝分裂细胞中的大多数是神经元。此外，在孵育和氟烷重新测试后，未观察到海马有丝分裂活性与动物最终表现出的癫痫发作类型之间存在相关性。在氟烷点燃的小鼠中，观察到海马有丝分裂活性与癫痫发作阈值之间存在显著相关性。总体而言，这些结果表明，一次和八次氟烷诱导的癫痫发作都是成年小鼠海马神经发生的有效诱导剂。结果进一步表明，海马神经发生的增加与行为性癫痫发作表型转变所依据的过程没有直接关系，但可能参与了这种氟烷癫痫发生模型中癫痫发作阈值的建立或维持。
