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, less than or equal to 2 00 muM) exhibit 1) spontaneous large inhibitory postsynaptic potentials (IP SPs) in pyramidal cells, which occur without the necessity of fast glutamat ergic receptors, and which hence are presumed to arise from coordinated fir ing in populations of interneurons; 2) spikes of variable amplitude, presum ed to be of antidromic origin, in some pyramidal cells during the large IPS P; 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, 3 84 interneurons), to examine how these phenomena might be inter-related. Ne twork bursts in electrically coupled interneurons have previously been show n to be possible with dendritic gap junctions, when the dendrites were capa ble of spike initiation, and when action potentials could cross from cell t o cell via gap junctions; recent experimental data showing that dendritic g ap junctions between cortical interneurons lead to coupling potentials of o nly about 0.5 mV argue against this mechanism, however. We now show that ax onal gap junctions between interneurons could also lead to network bursts; this concept is consistent with the occurrence of spikelets and partial spi kes in at least some interneurons in 4-AP. In our model, spontaneous antidr omic action potentials can induce spikelets and action potentials in princi pal cells during the large IPSP. The probability of observing this type of activity increases significantly when axonal gap junctions also exist betwe en pyramidal cells. Sufficient antidromic activity in the model can lead to epileptiform bursts, independent of alpha -amino-3-hydroxy-5-methyl-4-isox azolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, in so me principal cells, preceded by IPSPs and spikelets. The model predicts tha t gap junction blockers should suppress large IPSPs observed in 4-AP and sh ould also reduce the probability of observing antidromic activity, or burst ing, in pyramidal cells. Experiments show that, indeed, the gap junction bl ocking compound carbenoxolone does suppress spontaneous large IPSCs, occurr ing in 4-AP plus ionotropic glutamate blockers, together with a GABA(B) rec eptor blocker; carbenoxolone also suppresses large, fast inward currents, c orresponding to ectopic spikes, which occur in 4-AP. Carbenoxolone does not suppress large depolarizing IPSPs induced by tetanic stimulation. We concl ude that in 4-AP, axonal gap junctions could, at least in principle, accoun t in part for both the large IPSPs, and for the antidromic activity in pyra midal neurons.