The inhibitory effect of interleukin-1beta on long-term potentiation is coupled with increased activity of stress-activated protein kinases.

Long-term potentiation (LTP) in perforant path-granule cell synapses is decreased in aged rats, stressed rats, and rats injected intracerebroventricularly with the proinflammatory cytokine interleukin-1beta (IL-1beta). One factor that is common to these experimental conditions is an increase in the concentration of IL-1beta in the dentate gyrus, suggesting a causal relationship between the compromise in LTP and increased IL-1beta concentration. In this study, we have investigated the downstream consequences of an increase in IL-1beta concentration and report that the reduced LTP in rats injected intracerebroventricularly with IL-1beta was accompanied by a decrease in KCl-stimulated glutamate release in synaptosomes prepared from dentate gyrus, although unstimulated glutamate release was increased. These changes were paralleled by increased activity of the stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. Intracerebroventricular injection of IL-1beta increased reactive oxygen species production in hippocampal tissue, whereas IL-1beta and H(2)O(2) increased activities of both JNK and p38 in vitro. Dietary manipulation with antioxidant vitamins E and C blocked the increase in reactive oxygen species production, the stimulation of JNK and p38 activity, the attenuation of glutamate release, and the IL-1beta-induced inhibitory of LTP. We propose that IL-1beta stimulates activity of stress-activated kinases, which in turn may inhibit glutamate release and result in compromised LTP and that these actions are a consequence of increased production of reactive oxygen species.