Ferencz I, Kokaia M, Keep M, Elmér E, Metsis M, Kokaia Z, Lindvall O
Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.
Neuroscience. 1997 Sep;80(2):389-99. doi: 10.1016/s0306-4522(97)00006-7.
Intraventricular 192 IgG-saporin was used to induce a selective lesion of basal forebrain cholinergic neurons in rats. When subjected to 40 rapid hippocampal kindling stimulations with 5-min intervals, these animals exhibited increased number of generalized seizures and a higher mean seizure grade in response to the first five stimulations, and required fewer stimuli to develop focal behavioural seizures, as compared to non-lesioned rats. In contrast, both groups showed similarly enhanced responsiveness when test stimulated four weeks later. Using in situ hybridization, cholinergic denervation was found to cause a significant decrease of basal brain-derived neurotrophic factor messenger RNA levels in the hippocampal formation and piriform cortex, whereas gene expression for nerve growth factor, neurotrophin-3, and TrkB and TrkC was unchanged. Four weeks after rapid kindling stimulations, basal levels of brain-derived neurotrophic factor messenger RNA in the dentate granule cells were restored to normal in the lesioned rats, whereas neurotrophin-3 messenger RNA levels were decreased. No differences in the seizure-evoked levels of neurotrophin and Trk messenger RNAs were detected, except in the dentate granule cell layer, which had significantly higher brain-derived neurotrophic factor messenger RNA expression in the lesioned animals at 2 h. In conclusion, the basal forebrain cholinergic system (i) dampens the severity of recurring seizures induced by rapid hippocampal kindling stimulations, but has no effect on the subsequent delayed phase of epileptogenesis; and (ii) exerts a tonic stimulation of basal brain-derived neurotrophic factor messenger RNA levels in the hippocampal formation and piriform cortex. The findings also indicate that the cholinergic lesion does not affect neurotrophin and Trk gene expression after recurring seizures, and that the kindling process leads to long-term changes in basal brain-derived neurotrophic factor and neurotrophin-3 messenger RNA levels in the denervated animals.
脑室内注射192 IgG-皂草素用于诱导大鼠基底前脑胆碱能神经元的选择性损伤。当以5分钟的间隔进行40次快速海马点燃刺激时，与未损伤的大鼠相比，这些动物在前五次刺激时全身性癫痫发作的次数增加，平均癫痫发作等级更高，并且产生局灶性行为性癫痫发作所需的刺激次数更少。相比之下，四周后进行测试刺激时，两组动物的反应性均同样增强。通过原位杂交发现，胆碱能去神经支配导致海马结构和梨状皮质中脑源性神经营养因子信使核糖核酸水平显著降低，而神经生长因子、神经营养素-3以及TrkB和TrkC的基因表达未发生变化。快速点燃刺激四周后，损伤大鼠齿状颗粒细胞中脑源性神经营养因子信使核糖核酸的基础水平恢复正常，而神经营养素-3信使核糖核酸水平降低。除了在齿状颗粒细胞层，在损伤动物中2小时时脑源性神经营养因子信使核糖核酸表达显著更高外，未检测到神经营养因子和Trk信使核糖核酸在癫痫发作诱发水平上的差异。总之，基底前脑胆碱能系统（i）减轻快速海马点燃刺激诱发的反复癫痫发作的严重程度，但对随后的癫痫发生延迟期没有影响；（ii）对海马结构和梨状皮质中脑源性神经营养因子信使核糖核酸水平施加持续性刺激。研究结果还表明，胆碱能损伤在反复癫痫发作后不影响神经营养因子和Trk基因表达，并且点燃过程导致去神经支配动物中脑源性神经营养因子和神经营养素-3信使核糖核酸水平发生长期变化。
