Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency
Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency
复制标题
DOI：
10.1016/j.eplepsyres.2019.05.013
复制
发表时间：
2019-09-01
影响因子：
2.2
通讯作者：
Weinand, Martin E.
中科院分区：
文献类型：
--
作者：
Hammer, Michael F.;Sprissler, Ryan;Weinand, Martin E.
尽管最近我们对癫痫发生相关的突触传递的理解取得了进展，但控制颞叶癫痫（TLE）患者癫痫发作频率的分子机制仍然不清楚。对从12名医学上难治性TLE患者切除的海马组织进行RNA-Seq，这些患者的术前癫痫发作频率范围为每月0.33至120次癫痫发作。低发作频率（LSF，平均= 4次发作/月）与高发作频率（HSF，平均= 60次发作/月）个体的差异表达（DE）分析鉴定了979个转录丰度变化>= 2倍的基因（FDR调整的p值Δ 0.05）。与死后对照组的比较显示，HSF组（1676）与LSF组（399）中有大量下调的基因。超过50个信号通路被推断为失活或激活，信号转导是通路网络中的中心枢纽。虽然两组的神经炎症通路都被激活，但HSF组的关键神经系统通路系统性失活，包括钙、CREB和阿片样物质信号传导。我们还推断，促进突触降尺度的信号级联的表达增强可能在LSF队列中维持较高的癫痫发作阈值方面发挥了关键作用。这些结果表明，针对突触缩放通路的治疗方法可能有助于治疗TLE癫痫发作。
Despite recent advances in our understanding of synaptic transmission associated with epileptogenesis, the molecular mechanisms that control seizure frequency in patients with temporal lobe epilepsy (TLE) remain obscure. RNA-Seq was performed on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. Differential expression (DE) analysis of individuals with low (LSF, mean = 4 seizure/month) versus high (HSF, mean = 60 seizures/month) seizure frequency identified 979 genes with >= 2-fold change in transcript abundance (FDR-adjusted p-value delta 0.05). Comparisons with post-mortem controls revealed a large number of downregulated genes in the HSF (1676) versus LSF (399) groups. More than 50 signaling pathways were inferred to be deactivated or activated, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both groups, key neuronal system pathways were systematically deactivated in the HSF group, including calcium, CREB and Opioid signaling. We also infer that enhanced expression of a signaling cascade promoting synaptic downscaling may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE.