Fisher R S, Alger B E
J Neurosci. 1984 May;4(5):1312-23. doi: 10.1523/JNEUROSCI.04-05-01312.1984.
Depression of GABA-mediated IPSPs has been proposed to be a crucial factor in the onset of epileptiform activity in most models of epilepsy. To test this idea, we studied epileptiform activity induced by bath application of the excitatory neurotoxin kainic acid (KA) in the rat hippocampal slice. Repetitive field potential firing, spontaneous or evoked, occurred during exposure to KA. Intracellular records from 52 CA1 pyramidal cells during changes from control saline to saline containing 1 microM KA indicated that KA depolarized cells an average of about 5 mV and caused a 15% decrease in input resistance. Action potentials and current-induced burst afterhyperpolarizations did not change significantly. In several cells the tonic effects of KA were preceded by a transient phase of sporadic, spontaneous depolarizations of 2 to 10 mV and 50 to 200 msec duration. These phasic depolarizations were blocked by hyperpolarization. The major effect of 1 microM KA was a depression of synaptic potentials. Initially, KA depressed fast GABA-mediated IPSPs and slow, non-GABA-mediated late hyperpolarizing potentials to 23% and 40% of control values, respectively. IPSP depression correlated closely with onset of burst potential firing in response to synaptic stimulation. Similar observations were made on six cells from the CA2/3 region, although these cells were affected by lower doses of KA. The mechanism of IPSP depression was studied by using KCl-filled electrodes to invert spontaneous IPSPs and make them readily visible. In nine CA1 cells the rate and amplitude of spontaneous IPSPs transiently increased but then decreased in conjunction with evoked IPSP depression. Possible KA effects on postsynaptic GABA responses were investigated by applying GABA locally to cells. KA did not significantly affect GABA responses. Prolonged exposure of CA1 cells to KA in doses of 1 microM or higher depressed intracellularly and extracellularly recorded EPSPs and all field potential activity. This depression was not apparently due to depolarization block in CA1, however. We conclude that KA induces epileptiform activity in hippocampus principally by a presynaptic block of IPSP pathways.
在大多数癫痫模型中，γ-氨基丁酸（GABA）介导的抑制性突触后电位（IPSPs）降低被认为是癫痫样活动发作的关键因素。为了验证这一观点，我们研究了在大鼠海马切片中通过浴加兴奋性神经毒素海藻酸（KA）诱导的癫痫样活动。在暴露于KA期间，出现了重复性场电位发放，包括自发的和诱发的。在从对照生理盐水更换为含1微摩尔KA的生理盐水过程中，对52个CA1锥体细胞进行细胞内记录，结果表明KA使细胞平均去极化约5毫伏，并导致输入电阻降低15%。动作电位和电流诱发的爆发后超极化没有显著变化。在几个细胞中，KA的强直作用之前有一个短暂阶段，即出现2至10毫伏、持续50至200毫秒的散发性自发去极化。这些相位性去极化可被超极化阻断。1微摩尔KA的主要作用是抑制突触电位。最初，KA分别将快速GABA介导的IPSPs和缓慢的、非GABA介导的晚期超极化电位抑制至对照值的23%和40%。IPSP抑制与对突触刺激的爆发性电位发放的起始密切相关。在CA2/3区域的6个细胞上也有类似的观察结果，尽管这些细胞受较低剂量KA的影响。通过使用充满氯化钾的电极使自发IPSPs反转并使其易于观察，研究了IPSP抑制的机制。在9个CA1细胞中，自发IPSPs的频率和幅度短暂增加，但随后随着诱发IPSP抑制而降低。通过局部向细胞施加GABA，研究了KA对突触后GABA反应的可能影响。KA对GABA反应没有显著影响。将CA1细胞长时间暴露于1微摩尔或更高剂量的KA会抑制细胞内和细胞外记录的兴奋性突触后电位（EPSPs）以及所有场电位活动。然而，这种抑制显然不是由于CA1中的去极化阻滞。我们得出结论，KA主要通过IPSP通路的突触前阻滞在海马中诱导癫痫样活动。
