Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany,
Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany.
J Neurosci. 2019 Apr 24;39(17):3175-3187. doi: 10.1523/JNEUROSCI.1731-18.2019. Epub 2019 Feb 21.
Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca channel (VDCC) subunit Ca3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis. We found Egr1 to drive the expression of the VDCC subunit α2δ4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of α2δ4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 and α2δ4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of the VDCC subunits Ca3.2 and α2δ4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced "transcriptional Ca channelopathy." The onset of focal recurrent seizures often occurs after an epileptogenic process induced by transient insults to the brain. Recently, transcriptional control mechanisms for individual genes involved in converting neurons hyperexcitable have been identified, including early growth response 1 (Egr1), which activates transcription of the T-type Ca channel subunit Ca3.2. Here, we find Egr1 to regulate also the expression of the voltage-dependent Ca channel subunit α2δ4, which was augmented after pilocarpine- and kainic acid-induced status epilepticus. In addition, we observed that α2δ4 affected spontaneous network activity and the susceptibility for seizure induction. Furthermore, we detected corresponding dynamics in human biopsies from epilepsy patients. In conclusion, Egr1 orchestrates a seizure-induced "transcriptional Ca channelopathy" consisting of Ca3.2 and α2δ4, which act synergistically in epileptogenesis.
短暂性脑损伤，包括癫痫持续状态（SE），可引发癫痫发生期，在此期间神经元网络发生功能和结构重组，导致局灶性癫痫发作。近年来，调控癫痫发生过程中单个基因动态转录的机制已被阐明，这些机制有助于兴奋性神经元网络的发展。我们自己的研究结果表明，早期生长反应 1（Egr1）会短暂增加 T 型电压依赖性钙通道（VDCC）亚基 Ca3.2 的表达，Ca3.2 是一种关键的致癫痫蛋白。然而，癫痫发生涉及复杂和动态的转录组改变；到目前为止，我们对在相同过程中起作用的基因调控网络转录调控机制的理解还很有限。在这里，我们分析了 Egr1 是否作为参与癫痫发生过程中兴奋性增加的基因的关键转录调控因子。我们发现 Egr1 驱动 VDCC 亚基 α2δ4 的表达，在匹罗卡品诱导的 SE 后早期和持续增加。此外，我们表明，海马 CA1 区 α2δ4 水平的增加会通过轻微降低局部网络活动来增加小鼠的癫痫易感性。有趣的是，我们还在癫痫手术中获得的人类海马活检中检测到 Egr1 和 α2δ4 的表达水平增加。总之，Egr1 控制 VDCC 亚基 Ca3.2 和 α2δ4 的丰度，它们在癫痫发生中协同作用，从而导致癫痫诱导的“转录性钙通道病”。局灶性复发性癫痫的发作通常发生在短暂性脑损伤引起的癫痫发生过程之后。最近，已经确定了参与将神经元转变为过度兴奋的单个基因的转录控制机制，包括早期生长反应 1（Egr1），它激活 T 型钙通道亚基 Ca3.2 的转录。在这里，我们发现 Egr1 还调节电压依赖性钙通道亚基 α2δ4 的表达，α2δ4 在匹罗卡品和海人酸诱导的癫痫持续状态后增加。此外，我们观察到 α2δ4 影响自发网络活动和癫痫诱导的易感性。此外，我们在癫痫患者的活检中检测到相应的动态变化。总之，Egr1 协调由 Ca3.2 和 α2δ4 组成的癫痫诱导的“转录性钙通道病”，它们在癫痫发生中协同作用。
