The cytokine interleukin-6 (IL-6) may be a contributing mediator of CNS injury in several neurological disorders. To investigate the role of IL-6 in memory-related disorders, we examined transgenic mice (GFAP-IL6) with cerebral overexpression of IL-6 using paired-pulse facilitation, paired-pulse inhibition, and long-term potentiation (LTP) in an in vitro preparation. We found that paired-pulse potentiation and inhibition in the dentate gyrus of hippocampal slices prepared from the GFAP-IL6 mice did not differ significantly from age-matched control animals, suggesting that the increase in paired-pulse inhibition seen previously in in vivo studies of this model was due to alterations of afferents from other brain regions. However, LTP in the dentate was significantly reduced in slices from GFAP-IL6 transgenic mice when compared with littermate wild-type controls, providing support for a role of IL-6 in the pathogenesis of neurodegenerative associated memory-related disorders.