Powell Kim L, Ng Caroline, O'Brien Terence J, Xu Sheng Hong, Williams David A, Foote Simon J, Reid Christopher A
Department of Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Epilepsia. 2008 Oct;49(10):1686-95. doi: 10.1111/j.1528-1167.2008.01593.x. Epub 2008 Apr 7.
Studies in animal models and patients have implicated changes in hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) expression in the pathogenesis of temporal lobe epilepsy (TLE). However, the nature of HCN changes during the epileptogenic process and their commonality across different TLE models is unknown. Here HCN1 and HCN2 mRNA expression was quantitatively measured at different time points during epileptogenesis in two distinct animal models of TLE; the kainic acid (KA)-induced status epilepticus (SE) and amygdala kindling models.
Hippocampal subregions (CA1, CA3, and dentate gyrus [DG]) and entorhinal cortex were dissected at different time-points. For KA-induced SE animals this was 24 h, 7 days (preepileptic), and 6 weeks (epileptic) post status. For amygdala kindling animals this was 2 weeks after reaching either "partially kindled" (one class II/III seizure) or "fully kindled" (five class V seizures) states. Quantification of regional hippocampal neuronal loss in the KA-treated animals was done using NeuN immunofluorescence and confocal microscopy.
HCN mRNA levels decreased in an isoform and region specific manner at all time points after KA-induced SE. The decrease in neuronal number could not account for all reductions in HCN mRNA levels post-KA insult, implicating transcriptional changes. A reduction in HCN2 mRNA levels was also observed in fully kindled animals in the CA3 region.
A reduction in HCN mRNA levels is present in two different models of TLE. This supports the case that a reduction in HCN channel expression is an accompaniment of epileptogenesis in different adult models of TLE.
在动物模型和患者中的研究表明，超极化激活的环核苷酸门控阳离子通道（HCN）表达的变化与颞叶癫痫（TLE）的发病机制有关。然而，在致痫过程中HCN变化的性质以及它们在不同TLE模型中的共性尚不清楚。在此，我们在两种不同的TLE动物模型（红藻氨酸（KA）诱导的癫痫持续状态（SE）和杏仁核点燃模型）的致痫过程中的不同时间点，对HCN1和HCN2 mRNA表达进行了定量测量。
在不同时间点解剖海马亚区（CA1、CA3和齿状回[DG]）和内嗅皮质。对于KA诱导的SE动物，时间点为癫痫持续状态后24小时、7天（癫痫前期）和6周（癫痫期）。对于杏仁核点燃动物，时间点为达到“部分点燃”（一次II/III级发作）或“完全点燃”（五次V级发作）状态后2周。使用NeuN免疫荧光和共聚焦显微镜对KA处理动物的区域海马神经元损失进行定量。
KA诱导的SE后所有时间点，HCN mRNA水平均以亚型和区域特异性方式下降。神经元数量的减少不能解释KA损伤后HCN mRNA水平的所有降低，这意味着存在转录变化。在CA3区完全点燃的动物中也观察到HCN2 mRNA水平降低。
在两种不同的TLE模型中均存在HCN mRNA水平降低。这支持了HCN通道表达降低是不同成人TLE模型中癫痫发生伴随现象的观点。
