SELECTIVE SUPPRESSION OF IN-VITRO ELECTROGRAPHIC SEIZURES BY LOW-DOSETETRODOTOXIN - A NOVEL ANTICONVULSANT EFFECT

Localized injections of 50 mu M tetrodotoxin (TTX) in rat hippocampal slices blocked stimulus train-evoked electrographic seizures (EGSs) fo r several hours. Responses to single stimuli were minimally altered du ring TTX block of the EGSs. This selective reduction of epileptiform a ctivity could result from general blockade of action potentials in an anatomically distinct group of neurons in the slice. To test this hypo thesis, we systematically mapped TTX injection sites in the hippocampa l slice, and found that TTX injections that blocked EGSs were nearly a lways located in or invaded CA2/3 stratum radiatum and/or stratum lacu nosum-moleculare. A high degree of recurrent activity in this region c ontributes to both epileptiform activity and responses to single stimu li; hence our selective inhibition of EGSs suggests a more pharmacolog ically specific anticonvulsant effect of TTX. Consistent with this hyp othesis, 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/o r antidromic firing may be particularly vulnerable to TTX action on vo ltage-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.