Lopantsev Valeri, Both Martin, Draguhn Andreas
Institut für Physiologie und Pathophysiologie, Universität Heidelberg, Heidelberg, Germany.
Eur J Neurosci. 2009 Mar;29(6):1153-64. doi: 10.1111/j.1460-9568.2009.06663.x.
Epileptic seizures can induce pathological processes of plasticity in the brain that tend to promote the generation of further seizures. However, the immediate impact of epileptic seizures on cellular excitability remains poorly understood. In order to unravel such early mechanisms of epilepsy-induced plasticity, we studied synaptic transmission before and shortly after three ictal discharges induced by transient elevation of extracellular K(+) in mouse hippocampal slices. Discharges were initiated in the CA3 region and propagated via the Schaffer collaterals into CA1 where they were associated with sustained membrane depolarization and bursts of action potentials in CA1 pyramidal cells. Subsequently, discharges were followed by long-term potentiation (LTP) of Schaffer collateral-evoked field excitatory post-synaptic potentials (EPSPs) in the CA1. The ability to generate epileptiform activity in response to repetitive stimulation was enhanced during LTP. Changes in both inhibitory and excitatory synaptic transmission contributed to LTP in CA1 pyramidal cells. Discharges reduced gamma-aminobutyric acid-A receptor-mediated hyperpolarizing inhibitory post-synaptic potentials by shifting their reversal potentials in a positive direction. At the same time, the amplitudes of Schaffer collateral-evoked RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated EPSPs and action potential-independent miniature EPSPs were enhanced. However, N-methyl-d-aspartate receptor-mediated EPSPs remained unchanged. Paired-pulse stimulation revealed a reduced probability of glutamate release. Together, these changes in synaptic transmission produce a sustained increase in hippocampal excitability. We conclude that a few seizure-like ictal episodes are sufficient to cause fast and lasting changes in the excitation/inhibition balance in hippocampal networks, and therefore may contribute to early phases of progressive epileptogenesis.
癫痫发作可诱发大脑中的可塑性病理过程，这往往会促进更多癫痫发作的产生。然而，癫痫发作对细胞兴奋性的即时影响仍知之甚少。为了阐明癫痫诱发可塑性的早期机制，我们研究了小鼠海马切片中细胞外钾离子短暂升高诱发的三次发作性放电之前及之后不久的突触传递。放电在CA3区域起始，并通过谢弗侧支传播至CA1区，在CA1区它们与持续的膜去极化以及CA1锥体细胞的动作电位爆发相关。随后，放电之后CA1区出现了谢弗侧支诱发的场兴奋性突触后电位（EPSP）的长时程增强（LTP）。在LTP期间，对重复刺激产生癫痫样活动的能力增强。抑制性和兴奋性突触传递的变化均促成了CA1锥体细胞的LTP。放电通过将其反转电位正向移动，降低了γ-氨基丁酸-A受体介导的超极化抑制性突触后电位。与此同时，谢弗侧支诱发的RS-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的EPSP以及与动作电位无关的微小EPSP的幅度增强。然而，N-甲基-D-天冬氨酸受体介导的EPSP保持不变。双脉冲刺激显示谷氨酸释放的概率降低。总之，这些突触传递的变化使海马兴奋性持续增加。我们得出结论，少数癫痫样发作事件足以导致海马网络中兴奋/抑制平衡快速且持久的变化，因此可能促成进行性癫痫发生的早期阶段。
