Janz Philipp, Hauser Pascal, Heining Katharina, Nestel Sigrun, Kirsch Matthias, Egert Ulrich, Haas Carola A
Experimental Epilepsy Research, Department of Neurosurgery, University Medical Center, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Front Cell Neurosci. 2018 Aug 14;12:244. doi: 10.3389/fncel.2018.00244. eCollection 2018.
In mesial temporal lobe epilepsy (mTLE) an initial precipitating injury can trigger aberrant wiring of neuronal circuits causing seizure activity. While circuit reorganization is known to be largely activity-dependent, the interactions between neuronal activity and synaptic plasticity during the development of mTLE remain poorly understood. Therefore, the present study aimed at delineating the spatiotemporal relationship between epileptic activity, activity-dependent gene expression and synaptic plasticity during kainic acid-induced epileptogenesis in mice. We show that during epileptogenesis the sclerotic hippocampus differed from non-sclerotic regions by displaying a consistently lower power of paroxysmal discharges. However, the power of these discharges steadily increased during epileptogenesis. This increase was paralleled by the upregulation of the activity-related cytoskeleton protein () gene expression in dentate granule cells (DGCs) of the sclerotic hippocampus. Importantly, we found that mRNA-upregulating DGCs exhibited increased spine densities and spine sizes, but at the same time decreased AMPA-type glutamate receptor (AMPAR) densities. Finally, we show that optogenetic stimulation of DGC synapses evoked robust seizure activity in epileptic mice, but failed to induce dendritic translocation of mRNA as under healthy conditions, supporting the theory of a breakdown of the dentate gate in mTLE. We conclude that during epileptogenesis epileptic activity emerges early and persists in the whole hippocampus, however, only the sclerotic part shows modulation of discharge amplitudes accompanied by plasticity of DGCs. In this context, we identified as a putative mediator between seizure activity and synaptic plasticity.
在内侧颞叶癫痫（mTLE）中，最初的促发损伤可触发神经元回路的异常布线，从而导致癫痫发作活动。虽然已知回路重组在很大程度上依赖于活动，但在mTLE发展过程中神经元活动与突触可塑性之间的相互作用仍知之甚少。因此，本研究旨在描绘小鼠海藻酸诱导癫痫发生过程中癫痫活动、活动依赖性基因表达和突触可塑性之间的时空关系。我们发现，在癫痫发生过程中，硬化的海马体与非硬化区域不同，其阵发性放电的功率持续较低。然而，这些放电的功率在癫痫发生过程中稳步增加。这种增加与硬化海马体齿状颗粒细胞（DGCs）中与活动相关的细胞骨架蛋白（）基因表达的上调平行。重要的是，我们发现上调mRNA的DGCs表现出增加的棘突密度和棘突大小，但同时AMPA型谷氨酸受体（AMPAR）密度降低。最后，我们表明，对DGC突触进行光遗传学刺激可在癫痫小鼠中诱发强烈的癫痫发作活动，但在健康条件下未能诱导mRNA的树突移位，这支持了mTLE中齿状门破裂的理论。我们得出结论，在癫痫发生过程中，癫痫活动早期出现并在整个海马体中持续存在，然而，只有硬化部分表现出放电幅度的调节以及DGCs的可塑性。在此背景下，我们确定为癫痫发作活动和突触可塑性之间的假定介质。
