Behr J, Heinemann U, Mody I
Departments of Neurology and Physiology, Reed Neurological Research Center, UCLA School of Medicine, Los Angeles, California 90095-1769, USA.
J Neurophysiol. 2001 May;85(5):2195-202. doi: 10.1152/jn.2001.85.5.2195.
To elucidate the gating mechanism of the epileptic dentate gyrus on seizure-like input, we investigated dentate gyrus field potentials and granule cell excitatory postsynaptic potentials (EPSPs) following high-frequency stimulation (10-100 Hz) of the lateral perforant path in an experimental model of temporal lobe epilepsy (i.e., kindled rats). Although control slices showed steady EPSP depression at frequencies greater than 20 Hz, slices taken from animals 48 h after the last seizure presented pronounced EPSP facilitation at 50 and 100 Hz, followed by steady depression. However, 28 days after kindling, the EPSP facilitation was no longer detectable. Using the specific N-methyl-D-aspartate (NMDA) and RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponic acid (AMPA) receptor antagonists 2-amino-5-phosphonovaleric acid and SYM 2206, we examined the time course of alterations in glutamate receptor-dependent synaptic currents that parallel transient EPSP facilitation. Forty-eight hours after kindling, the fractional AMPA and NMDA receptor-mediated excitatory postsynaptic current (EPSC) components shifted dramatically in favor of the NMDA receptor-mediated response. Four weeks after kindling, however, AMPA and NMDA receptor-mediated EPSCs reverted to control-like values. Although the granule cells of the dentate gyrus contain mRNA-encoding kainate receptors, neither single nor repetitive perforant path stimuli evoked kainate receptor-mediated EPSCs in control or in kindled rats. The enhanced excitability of the kindled dentate gyrus 48 h after the last seizure, as well as the breakdown of its gating function, appear to result from transiently enhanced NMDA receptor activation that provides significantly slower EPSC kinetics than those observed in control slices and in slices from kindled animals with a 28-day seizure-free interval. Therefore, NMDA receptors seem to play a critical role in the acute throughput of seizure activity and in the induction of the kindled state but not in the persistence of enhanced seizure susceptibility.
为了阐明癫痫齿状回对癫痫样输入的门控机制，我们在颞叶癫痫实验模型（即点燃大鼠）中，研究了高频刺激（10 - 100 Hz）外侧穿通路径后齿状回场电位和颗粒细胞兴奋性突触后电位（EPSP）。尽管对照切片在频率大于20 Hz时显示出稳定的EPSP抑制，但在最后一次癫痫发作后48小时取自动物的切片在50和100 Hz时呈现出明显的EPSP易化，随后是稳定的抑制。然而，点燃后28天，EPSP易化不再可检测到。使用特异性N - 甲基 - D - 天冬氨酸（NMDA）和RS - α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸（AMPA）受体拮抗剂2 - 氨基 - 5 - 磷酸戊酸和SYM 2206，我们研究了与短暂EPSP易化平行的谷氨酸受体依赖性突触电流变化的时间进程。点燃后48小时，AMPA和NMDA受体介导的兴奋性突触后电流（EPSC）成分的分数显著向有利于NMDA受体介导的反应方向转变。然而，点燃后四周，AMPA和NMDA受体介导的EPSC恢复到类似对照的值。尽管齿状回的颗粒细胞含有编码海人藻酸受体的mRNA，但在对照或点燃大鼠中，单次或重复的穿通路径刺激均未诱发海人藻酸受体介导的EPSC。最后一次癫痫发作后48小时点燃的齿状回兴奋性增强，以及其门控功能的破坏，似乎是由于NMDA受体激活短暂增强所致，与对照切片以及间隔28天无癫痫发作的点燃动物的切片相比，NMDA受体激活导致EPSC动力学明显减慢。因此，NMDA受体似乎在癫痫活动的急性通过和点燃状态的诱导中起关键作用，但在增强的癫痫易感性的持续中不起作用。
