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.
Vereker
E
E
Department of Physiology, Trinity College, Dublin 2, Ireland.
O'Donnell
E
E
Lynch
M A
MA
D000704:Analysis of Variance; D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000032:analysis; D019587:Dietary Supplements; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects; D011189:Potassium Chloride / Q000008:administration & dosage; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013569:Synapses / Q000187:drug effects; D013574:Synaptosomes / Q000378:metabolism; D014810:Vitamin E / Q000008:administration & dosage / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D017382:Reactive Oxygen Species; D014810:Vitamin E; D018698:Glutamic Acid; D011189:Potassium Chloride; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid