Synaptic and nonsynaptic contributions to giant ipsps and ectopic spikes induced by 4-aminopyridine in the hippocampus in vitro.
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.
Department of Pharmacology, Division of Neuroscience, University of Birmingham School of Medicine, Edgbaston, Birmingham B15 2TT, United Kingdom. r.d.traub@bham.ac.uk
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D015761:4-Aminopyridine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology; D002229:Carbenoxolone / Q000494:pharmacology; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D016571:Neural Networks, Computer; D026902:Potassium Channel Blockers; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D058788:GABA-B Receptor Antagonists; D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D002229:Carbenoxolone