Department of Neurology, University of Virginia, Charlottesville, VA, USA.
Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
Epilepsia. 2018 Oct;59 Suppl 2(Suppl 2):78-81. doi: 10.1111/epi.14482. Epub 2018 Aug 29.
Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced γ-aminobutyric acid type A receptor-mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known. We propose that insertion of GluA1 subunits at the glutamatergic synapses causes potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR)-mediated neurotransmission, which helps to spread and sustain seizures. The AMPAR-mediated neurotransmission of CA1 pyramidal neurons was increased in animals in SE induced by pilocarpine. The surface membrane expression of GluA1 subunit-containing AMPARs on CA1 pyramidal neurons was also increased. Blockade of N-methyl-d-aspartate receptors 10 minutes after the onset of continuous electrographic seizure activity prevented the increase in the surface expression of GluA1 subunits. N-methyl-d-aspartate receptor antagonist MK-801 in conjunction with diazepam also terminated seizures that were refractory to MK-801 or diazepam alone. Future studies using mice lacking the GluA1 subunit expression will provide further insights into the role of GluA1 subunit-containing AMPAR plasticity in sustaining seizures of SE.
癫痫持续状态（SE）的长时间发作是由于发作终止机制的失败或维持发作的机制被激活所致。γ-氨基丁酸 A 型受体介导的突触传递减少导致发作终止受损。然而，持续长时间发作的机制尚不清楚。我们提出，谷氨酸能突触中 GluA1 亚基的插入导致 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）介导的神经传递增强，这有助于传播和维持发作。在匹鲁卡品诱导的 SE 动物中，CA1 锥体神经元的 AMPAR 介导的神经传递增加。CA1 锥体神经元上含有 GluA1 亚基的 AMPAR 的表面膜表达也增加。在持续电描记发作活动开始后 10 分钟阻断 N-甲基-D-天冬氨酸受体 1 型可防止 GluA1 亚基表面表达的增加。N-甲基-D-天冬氨酸受体拮抗剂 MK-801 与地西泮联合使用也终止了对 MK-801 或地西泮单独耐药的发作。使用缺乏 GluA1 亚基表达的小鼠进行的未来研究将进一步深入了解含有 GluA1 亚基的 AMPAR 可塑性在维持 SE 发作中的作用。
