We have determined whether seizures generate an epileptogenic focus in distal structures using an in vitro preparation composed of three independent chambers that accommodate two intact hippocampi and their connecting commissures. This enabled us to apply a convulsive agent to one hippocampus, allow the propagation of a given number of seizures to the other side and block the connections reversibly by applying tetrodotoxin (TTX) to the commissural chamber. The propagation of seizures from the kainate-treated side to the naive side transformed the latter into an independent epileptogenic focus that was capable of generating spontaneous and evoked seizures. The induction mechanism required activation of NMDA receptors and the epileptogenic transformation was associated with long-term alterations in GABAergic synapses, which became excitatory because of a shift in the chloride reversal potential, E(Cl). These data indicate that the excitatory actions of GABA may be a fundamental property of epileptogenic structures.