Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, Saint Petersburg 194223, Russia.
Int J Mol Sci. 2021 Dec 12;22(24):13355. doi: 10.3390/ijms222413355.
Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium-pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium-pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron-astrocyte interactions plays a critical role in the impairment of synaptic plasticity.
癫痫持续状态（SE）导致神经元网络功能持续异常，常导致癫痫发作恶化。癫痫诱导变化的许多细胞和分子机制细节仍然未知。锂-匹罗卡品大鼠癫痫模型再现了人类颞叶癫痫的许多特征。在这项工作中，我们使用锂-匹罗卡品模型在三周大的大鼠中，检查了匹罗卡品诱导癫痫发作后一周内海马体的形态和电生理变化。我们发现，海马体和齿状回中有近三分之一的神经元在第一天死亡，但此时突触可塑性没有受损。三天后观察到长时程增强（LTP）减弱，SE 对可塑性的负面影响一周后增加，同时伴有星形胶质细胞增生。LTP 的衰减是由于 N-甲基-D-天冬氨酸受体（NMDAR）依赖性信号转导减弱所致。与对照组相比，SE 后大鼠在高频刺激期间的 NMDAR 电流弱了两倍多。应用神经胶质递质 D-丝氨酸，一种 NMDAR 的共激动剂，可以增强 NMDAR 依赖性电流并恢复 LTP。这些结果表明，神经元-星形胶质细胞相互作用的紊乱在突触可塑性损伤中起关键作用。
