Recent evidence suggests that interleukin-1beta (IL-1beta), which was originally identified as a proinflammatory cytokine, is also required in the brain for memory processes. We have previously shown that IL-1beta synthesis in the hippocampus is dependent on P2X(7) receptor (P2X(7)R), which is an ionotropic receptor of ATP. To substantiate the role of P2X(7)R in both brain IL-1beta expression and memory processes, we examined the induction of IL-1beta mRNA expression in the hippocampus of wild-type (WT) and homozygous P2X(7) receptor knockout mice (P2X(7)R(-/-)) following a spatial memory task. The spatial recognition task induced both IL-1beta mRNA expression and c-Fos protein activation in the hippocampus of WT but not of P2X(7)R(-/-) mice. Remarkably, P2X(7)R(-/-) mice displayed spatial memory impairment in a hippocampal-dependant task, while their performances in an object recognition task were unaltered. Taken together, our results show that P2X(7)R plays a critical role in spatial memory processes and the associated hippocampal IL-1beta mRNA synthesis and c-Fos activation.