To learn whether epileptic seizures in Rasmussen encephalitis (RE) may be promoted by insufficient γ-aminobutyric acid (GABA) release. 3H-GABA was released from neocortical synaptosomes through transporter reversal following intrasynaptosomal Na+ accumulation by veratridine that prevents inactivation of Na+ channels. Tissues of three RE patients were compared with those of nine non-RE. In RE, the release was markedly reduced. In non-RE, the extracellular Ca2+ concentration ([Ca2+]e) was inversely related to the amount of release. In RE, the percental decline of additional release upon withdrawal was linked with the presurgical duration of epilepsy. Permanent opening of Na+ channels by veratridine resembles maximal frequency of action potentials corresponding to epileptic seizures. These are preceded by a fall in [Ca2+]e. Zero [Ca2+]e increased release through the Na+/Ca2+ exchanger additionally elevating intrasynaptosomal Na+. This enhanced GABA release probably reflects an antiseizure mechanism. In RE, the additional release gets lost over epilepsy duration.