Several similarities exist between the alterations observed in the chronic pilocarpine model of recurrent seizures in the rat and those found in human temporal lobe epilepsy. The present studies are focused on changes in the GABA system in this model. Following the initial pilocarpine-induced seizures, a substantial loss of glutamic acid decarboxylase (GAD) mRNA-containing neurons has been found in the hilus of the dentate gyrus (Obenaus et al., J. Neurosci., 13 (1993) 4470-4485), and, recently, a loss of GAD mRNA-labeled neurons has also been found in stratum oriens of CA1. Yet numerous other GABA neurons remain within the hippocampal formation, and there appear to be multiple compensatory changes in these neurons. Labeling for GAD65 mRNA and associated protein is substantially increased in the remaining GABA neurons at 2-4 months after the initial seizure episode. Such increased labeling suggests that the remaining GABA neurons are part of a functional circuit and may be responding to the need for increased activity. Alterations also occur in at least one subunit of the GABA-A receptor. Labeling for the alpha(5) subunit mRNA is substantially decreased in CA1 and CA2 of pilocarpine-treated rats during the chronic, seizure-prone period. These findings emphasize the complexity of changes in the GABA system and indicate a need for evaluating the functional consequences of each of the changes. The initial loss of specific groups of GABA neurons could be a critical first step in the gradual development of epileptiform activity. While many of the subsequent changes in the GABA system may be considered to be compensatory, significant deficits of GABAergic function could remain.