1Neurology Department, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, Hunan, China.
Neurochem Res. 2018 Apr;43(4):878-885. doi: 10.1007/s11064-018-2493-z. Epub 2018 Feb 21.
Cortical dysplasia is the most common etiology of intractable epilepsy. Both excitability changes in cortical neurons and neural network reconstitution play a role in cortical dysplasia epileptogenesis. Recent research shows that the axon initial segment, a subcompartment of the neuron important to the shaping of action potentials, adjusts its position in response to changes in input, which contributes to neuronal excitability and local circuit balance. It is unknown whether axon initial segment plasticity occurs in neurons involved in seizure susceptibility in cortical dysplasia. Here, we developed a "Carmustine"- "pilocarpine" rat model of cortical dysplasia and show that it exhibits a lower seizure threshold, as indicated by behavior studies and electroencephalogram monitoring. Using immunofluorescence, we measured the axon initial segment positions of deep L5 somatosensory neurons and show that it is positioned closer to the soma after acute seizure, and that this displacement is sustained in the chronic phase. We then show that Nifedipine has a dose-dependent protective effect against axon initial segment displacement and increased seizure susceptibility. These findings further our understanding of the pathophysiology of seizures in cortical dysplasia and suggests Nifedipine as a potential therapeutic agent.
皮质发育不良是难治性癫痫最常见的病因。皮质神经元兴奋性改变和神经网络重构在皮质发育不良致痫中起作用。最近的研究表明，轴突起始段是神经元的一个亚区，对动作电位的形成很重要，它会根据输入的变化调整位置，从而有助于神经元兴奋性和局部回路平衡。目前尚不清楚皮质发育不良中参与癫痫易感性的神经元是否存在轴突起始段可塑性。在这里，我们开发了一种“卡莫司汀”-“毛果芸香碱”大鼠皮质发育不良模型，并通过行为研究和脑电图监测表明，它表现出较低的癫痫发作阈值。通过免疫荧光，我们测量了深部 L5 体感神经元的轴突起始段位置，并表明急性癫痫后它更靠近胞体，并且这种位移在慢性期持续存在。然后我们表明硝苯地平对轴突起始段位移和增加的癫痫易感性具有剂量依赖性的保护作用。这些发现进一步了解了皮质发育不良中癫痫发作的病理生理学，并表明硝苯地平可能是一种潜在的治疗药物。
