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J. Biol. Chem., Vol. 278, Issue 21, 19453-19462, May 23, 2003

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Activation of p38 Plays a Pivotal Role in the Inhibitory Effect of Lipopolysaccharide and Interleukin-1 on Long Term Potentiation in Rat Dentate Gyrus^*

Áine Kelly , Emily Vereker, Yvonne Nolan, Marcella Brady, Claire Barry, Christine E. Loscher , Kingston H. G. Mills  and Marina A. Lynch

From the Trinity College Institute of Neuroscience, Department of Physiology, Dublin 2, Ireland, Department of Biochemistry, Trinity College, Dublin 2, Ireland

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 (IL-1). The LPS-induced effects were abrogated by inhibition of caspase-1, suggesting that IL-1 may mediate the effects of LPS. Here we report that the inhibition of LTP induced by LPS and IL-1 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 B (NFB), may play a role, since the inhibitory effect of LPS and IL-1 on LTP was attenuated by the NFB inhibitor, SN50; consistently, LPS and IL-1 led to activation of NFB in entorhinal cortex. We suggest that one consequence of these LPS and IL-1-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 and is a consequence of activation of p38.

Received for publication, February 24, 2003

To whom correspondence should be addressed. Tel.: 353-1-6083794/6081019; Fax: 353-1-6793545; E-mail: aikelly{at}tcd.ie.

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