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Localized injections of 50 μM tetrodotoxin (TTX) in rat hippocampal slices blocked stimulus train-evoked electrographic seizures (EGSs) for several hours. Responses to single stimuli were minimally altered during TTX block of the EGSs. This selective reduction of epileptiform activity could result from general blockade of action potentials in an anatomically distinct group of neurons in the slice. To test this hypothesis, we systematically mapped TTX injection sites in the hippocampal slice, and found that TTX injections that blocked EGSs were nearly always located in or invaded CA2/3 stratum radiatum and/or stratum lacunosum-moleculare. A high degree of recurrent activity in this region contributes to both epileptiform activity and responses to single stimuli; hence our selective inhibition of EGSs suggests a more pharmacologically specific anticonvulsant effect of TTX. Consistent with this hypothesis, we found that low concentrations of TTX (5, 10, or 20 nM) in the perfusion medium blocked EGSs without decreasing the amplitude of extracellular responses to single stimuli. Polysynaptic activity and/or antidromic firing may be particularly vulnerable to TTX action on voltage-gated sodium channels, due to their lower the safety factor for action potential propagation. Selective reduction of this activity may disrupt the abnormal neuronal activity underlying EGSs.