Recent evidence has emphasised the importance of mitogen-activated protein kinase activation in the modulation of hippocampal synaptic plasticity. Whilst extracellular-regulated kinase activation is now regarded as a critical step in the induction of long-term potentiation (LTP), activation of p38 and c-Jun N-terminal kinase (JNK) is associated with its inhibition. Here, the effects of the novel JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-1 (SP600125) were investigated on the inhibition of LTP by cytokines interleukin-1beta, interleukin-18 and tumour necrosis factor-alpha in the dentate gyrus. Perfusion of SP600125 alone prior to tetanic stimulation of the medial perforant path did not significantly affect baseline synaptic transmission, post-tetanic potentiation or the magnitude of induced LTP. When SP600125 was perfused onto slices prior to application of cytokines, this resulted in a complete reversal of the cytokine-mediated inhibition of LTP. Moreover, the magnitude of LTP attained in these slices was significantly greater than that obtained in vehicle control slices. Next, we investigated the effects of the JNK inhibitor on the impairment of pharmacologically isolated N-methyl-D-aspartate receptor-mediated potentials (NMDA-EPSPs) by interleukin-18. Whilst not affecting baseline amplitude when perfused alone, prior perfusion of SP600125 alleviated the depressive effect of interleukin-18 on NMDA-EPSPs. Finally, we examined the possibility of JNK involvement in the induction of long-term depression (LTD) in the dentate gyrus. Perfusion of SP600125 prior to low-frequency stimulation of the perforant path resulted in a significant attenuation of induced LTD, which suggests that JNK activation is a critical mediator of LTD in the dentate gyrus. These results directly implicate, for the first time, differential activation of JNK in the modulation of distinct forms of hippocampal synaptic plasticity. Whereas acute over-activation of JNK by pathophysiological concentrations of cytokines is detrimental to LTP, physiologic activation of JNK appears necessary for the induction of LTD.