Traub R D, Bibbig R, Piechotta A, Draguhn R, Schmitz D
Department of Pharmacology, Division of Neuroscience, University of Birmingham School of Medicine, Edgbaston, Birmingham B15 2TT, United Kingdom.
J Neurophysiol. 2001 Mar;85(3):1246-56. doi: 10.1152/jn.2001.85.3.1246.
Hippocampal slices bathed in 4-aminopyridine (4-AP, < or =200 microM) exhibit 1) spontaneous large inhibitory postsynaptic potentials (IPSPs) in pyramidal cells, which occur without the necessity of fast glutamatergic receptors, and which hence are presumed to arise from coordinated firing in populations of interneurons; 2) spikes of variable amplitude, presumed to be of antidromic origin, in some pyramidal cells during the large IPSP; 3) bursts of action potentials in selected populations of interneurons, occurring independently of fast glutamatergic and of GABA(A) receptors. We have used neuron pairs, and a large network model (3,072 pyramidal cells, 384 interneurons), to examine how these phenomena might be inter-related. Network bursts in electrically coupled interneurons have previously been shown to be possible with dendritic gap junctions, when the dendrites were capable of spike initiation, and when action potentials could cross from cell to cell via gap junctions; recent experimental data showing that dendritic gap junctions between cortical interneurons lead to coupling potentials of only about 0.5 mV argue against this mechanism, however. We now show that axonal gap junctions between interneurons could also lead to network bursts; this concept is consistent with the occurrence of spikelets and partial spikes in at least some interneurons in 4-AP. In our model, spontaneous antidromic action potentials can induce spikelets and action potentials in principal cells during the large IPSP. The probability of observing this type of activity increases significantly when axonal gap junctions also exist between pyramidal cells. Sufficient antidromic activity in the model can lead to epileptiform bursts, independent of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, in some principal cells, preceded by IPSPs and spikelets. The model predicts that gap junction blockers should suppress large IPSPs observed in 4-AP and should also reduce the probability of observing antidromic activity, or bursting, in pyramidal cells. Experiments show that, indeed, the gap junction blocking compound carbenoxolone does suppress spontaneous large IPSCs, occurring in 4-AP plus ionotropic glutamate blockers, together with a GABA(B) receptor blocker; carbenoxolone also suppresses large, fast inward currents, corresponding to ectopic spikes, which occur in 4-AP. Carbenoxolone does not suppress large depolarizing IPSPs induced by tetanic stimulation. We conclude that in 4-AP, axonal gap junctions could, at least in principle, account in part for both the large IPSPs, and for the antidromic activity in pyramidal neurons.
浸泡在4-氨基吡啶（4-AP，≤200微摩尔）中的海马切片表现出：1）锥体细胞中自发的大抑制性突触后电位（IPSPs），其产生无需快速谷氨酸能受体，因此推测是由中间神经元群体的协同放电引起的；2）在大IPSP期间，一些锥体细胞中出现幅度可变的尖峰，推测为逆行性起源；3）选定的中间神经元群体中动作电位的爆发，其发生独立于快速谷氨酸能和GABAA受体。我们使用神经元对和一个大型网络模型（3072个锥体细胞，384个中间神经元）来研究这些现象可能如何相互关联。先前已表明，当树突能够引发尖峰且动作电位可通过缝隙连接在细胞间传递时，电耦合中间神经元中的网络爆发通过树突缝隙连接是可能的；然而，最近的实验数据表明，皮质中间神经元之间的树突缝隙连接仅导致约0.5毫伏的耦合电位，这与该机制相悖。我们现在表明，中间神经元之间的轴突缝隙连接也可导致网络爆发；这一概念与4-AP中至少一些中间神经元中出现的小尖峰和部分尖峰一致。在我们的模型中，自发的逆行性动作电位可在大IPSP期间诱导主细胞中的小尖峰和动作电位。当锥体细胞之间也存在轴突缝隙连接时，观察到这种活动类型的概率会显著增加。模型中足够的逆行性活动可导致一些主细胞中出现癫痫样爆发，独立于α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和N-甲基-D-天冬氨酸（NMDA）受体，爆发之前会出现IPSPs和小尖峰。该模型预测，缝隙连接阻滞剂应抑制在4-AP中观察到的大IPSPs，还应降低在锥体细胞中观察到逆行性活动或爆发的概率。实验表明，事实上，缝隙连接阻断化合物甘草次酸确实抑制了在4-AP加离子型谷氨酸受体阻滞剂以及GABAB受体阻滞剂存在时出现的自发大IPSCs；甘草次酸还抑制了在4-AP中出现的与异位尖峰相对应的大的快速内向电流。甘草次酸不抑制强直刺激诱导的大去极化IPSPs。我们得出结论，在4-AP中，轴突缝隙连接至少在原则上可以部分解释大IPSPs以及锥体细胞中的逆行性活动。
