Objective: It is known that highly activated microglia and the consequent production of inflammatory cytokines were associated with neuroexcitotoxic injuries. The present study was carried out to explore whether interleukin-1 beta (IL-1 beta), a proinflammatory cytokine produced in abundance by activated microglia, mediates increased excitability of hippocampal neurons and the related molecular mechanisms. Methods: Primary cultured microglia were activated by kainic acid (KA), and the KA-treated microglial conditioned medium (KA-MCM) was collected. KA-MCM with or without anti-rat IL-1 beta monoclonal neutralizing antibody was then injected into the rat in the right cerebral ventricle, or primary cultured hippocampal neurons were treated with the above-mentioned KA-MCM. The population spike amplitude changes in the CA3 region were assessed by electrophysiological recording in vivo. Western blot and RT-PCR assay were performed to investigate the expression changes of N-methyl-D-aspartate receptor subunit 1 (NMDAR1) and inducible nitric oxide synthase (iNOS) expression in hippocampal neurons. Results: Primary cultured microglia were significantly activated by KA with increased IL-1 beta levels. Interestingly, intracerebroventricular administration of KA-MCM to rats resulted in enhancement of population spike amplitude in the CA3 region and in upregulation of NMDAR1 and iNOS expression in the hippocampus, which was partially attenuated by anti-rat IL-1 beta antibody. Furthermore, the changes in NMDAR1 and iNOS expression in the rat hippocampus were verified by incubation of primary cultured hippocampal neurons with KA-MCM. Conclusion: This study provides evidence that KA-activated microglia mediate increased excitability of hippocampal neurons in vitro and in vivo and that IL-1 beta may be one of the main causes of this event. Copyright (C) 2009 S. Karger AG, Basel