Fast responses to extracellular ATP are mediated by the activation of P2X receptors. Native and cloned P2X receptors are permeable to monovalent cations such as Na+ and K+ as well as divalent cations such as Ca2+. However, altered P2X receptor expression has not been definitively determined under pathological conditions, particularly in epilepsy. Here we show that, in the seizure-sensitive (SS) gerbil hippocampus, a recognized genetic epilepsy model, the expressions of both P2X2 and P2X4 receptors are markedly decreased as compared with that in the seizure-resistant (SR) gerbil. These alterations are closely related to changes in gamma-aminobutyric acid (GABA) concentrations induced by vigabatrin (VGB) or 3-mercaptopropionic acid (3-MPA) treatment. Furthermore, the regulation of both P2X receptor expression in the gerbil hippocampus was mediated by the GABA(A) receptor, not GABA(B). These results suggest that the GABA(A) receptor-mediated modulation of P2X receptor expression may play an important role in the regulation of neuronal excitability.