Glutamate receptors mediate TTX-resistant synchronous activity in the rat hippocampus.

4-Aminopyridine (4-AP) is a well known convulsant that enhances the release of both excitatory and inhibitory neurotransmitters in the CNS. Low concentrations of 4-AP (approximately 100 microM) readily induce synchronized discharges in the hippocampus that are blocked by tetrodotoxin (TTX), suggesting that they require Na(+)-dependent action potentials in addition to the enhanced release of neurotransmitters. However, in the present study we have found that higher concentrations of 4-AP (1 mM) in combination with 5 mM tetraethylammonium (TEA) induce spontaneous synchronized discharges in rat hippocampal slices that are resistant to blockade by TTX. These synchronous discharges are evident in field potential recordings, which progress from the hilus to CA1 at 0.023 +/- 0.002 m/sec and in intracellular recordings from the hilar mossy cells and CA3 pyramidal cells. In some slices exposed to 4-AP and TEA, smaller-amplitude asynchronous responses also were recorded. 4-AP-induced spontaneous discharges are blocked by 20 microM DNQX and by 100 microM Cd(2+) but are resistant to blockade by either 25 microM bicuculline or 25 microM D-APV. These results suggest that the activation of postsynaptic AMPA receptors is necessary to produce TTX-resistant synchronized discharges. The laminar profile of field potentials recorded in CA3 and CA1 suggests that glutamate is released from axons of CA3 pyramidal cells despite the blockade of fast axonal Na(+) channels by TTX. Synchronous discharges may result from glutamate released at proximal recurrent collaterals after spontaneous Ca(2+) spikes in CA3 pyramidal cells.