title: Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1 beta on long term potentiation in rat dentate gyrus.
abstract: Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, has been shown to induce profound changes both peripherally and centrally. It has recently been reported that intraperitoneal injection of LPS inhibited long term potentiation (LTP) in perforant path-granule cell synapses and that this effect was coupled with an increase in the concentration of the proinflammatory cytokine, interleukin-1 beta (IL-1 beta). The LPS-induced effects were abrogated by inhibition of caspase-1, suggesting that IL-1 beta may mediate the effects of LPS. Here we report that the inhibition of LTP induced by LPS and IL-1 beta was coupled with stimulation of the stress-activated protein kinase p38 in hippocampus and entorhinal cortex and that this effect was abrogated by the p38 inhibitor SB203580, while the effect of LPS was markedly attenuated in C57BL/6 IL-1RI-/- mice. The data also indicate that activation of the transcription factor, nuclear factor kappa B (NF kappa B), may play a role, since the inhibitory effect of LPS and IL-1 beta on LTP was attenuated by the NF kappa B inhibitor, SN50; consistently, LPS and IL-1 beta led to activation of NF kappa B in entorhinal cortex. We suggest that one consequence of these LPS and IL-1 beta-induced changes is a compromise in glutamate release in dentate gyrus, which was coupled with the inhibition of LTP. The evidence is consistent with the idea that the LPS-induced impairment in LTP is mediated by IL-1 beta and is a consequence of activation of p38.
authors.affiliation: Trinity College Institute of Neuroscience, Department of Physiology, Dublin 2, Ireland. aikelly@tcd.ie
authors.forename: Aine
authors.initials: A
authors.lastname: Kelly
authors.forename: Emily
authors.initials: E
authors.lastname: Vereker
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nolan
authors.forename: Marcella
authors.initials: M
authors.lastname: Brady
authors.forename: Claire
authors.initials: C
authors.lastname: Barry
authors.forename: Christine E
authors.initials: CE
authors.lastname: Loscher
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D018728:Entorhinal Cortex / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020170:Caspase 1; C093642:SB 203580