The inhibitory effect of interleukin-1 beta 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 dec reased in aged rats, stressed rats, and rats injected intracerebroventricul arly with the proinflammatory cytokine interleukin-1 beta (IL-1 beta). One factor that is common to these experimental conditions is an increase in th e concentration of IL-1 beta in the dentate gyrus, suggesting a causal rela tionship between the compromise in LTP and increased IL-1 beta concentratio n. In this study, we have investigated the downstream consequences of an in crease in IL-1 beta concentration and report that the reduced LTP in rats i njected intracerebroventricularly with IL-1 beta was accompanied by a decre ase in KCl-stimulated glutamate release in synaptosomes prepared from denta te gyrus, although unstimulated glutamate release was increased. These chan ges were paralleled by increased activity of the stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. Int racerebroventricular injection of IL-1 beta increased reactive oxygen speci es production in hippocampal tissue, whereas IL-1 beta and H2O2 increased a ctivities of both JNK and p38 in vitro. Dietary manipulation with antioxida nt vitamins E and C blocked the increase in reactive oxygen species product ion, the stimulation of JNK and p38 activity, the attenuation of glutamate release, and the IL-1 beta-induced inhibitory of LTP. We propose that IL-1 beta stimulates activity of stress-activated kinases, which in turn may inh ibit glutamate release and result in compromised LTP and that these actions are a consequence of increased production of reactive oxygen species.