Rd. Traub et al., Synaptic and nonsynaptic contributions to giant IPSPs and ectopic spikes induced by 4-aminopyridine in the hippocampus in vitro, J NEUROPHYS, 85(3), 2001, pp. 1246-1256
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.