The p38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1β on longterm potentiation in the rat dentate gyrus in vitro

Levels of the pro-inflammatory cytokine interleukin-1 beta are known to be elevated in patients with chronic disorders such as Alzheimer's disease. We have investigated the effects of interleukin-1 beta on long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials in the rat dentate gyrus in vitro utilizing field extracellular recordings obtained from the middle third of the molecular layer of the dentate gyrus. Presynaptic stimulation was applied to the commissural/association pathway at a frequency of 0.05 Hz and at a distance of 50 mu m from the granule cell body layer. As previously reported, interleukin-1 beta (1 ng/ml) caused an inhibition of long-term potentiation (108 +/- 2% of baseline 1 h following application of tetanic stimulation compared with 145 +/- 5% in vehicle control slices). This action of interleukin-1 beta on long-term potentiation, as well as an inhibition of N-methyl-D-aspartate receptor-mediated field potentials, was attenuated by pre-treatment of slices with the p38 mitogen-associated protein kinase inhibitor SB203580 (1 mu M) SB203580 alone had no significant affect on long-term potentiation, but did cause an increase in baseline synaptic transmission [107 +/- 2% of baseline, 1 h after SB203580 (1 mu M) treatment]. The p42/44 mitogen-activated protein kinase cascade inhibitor PD98059 (50 mu M) did not inhibit the interleukin-1 beta-induced inhibition of N-methyl-D-aspartate receptor-mediated field potentials. The cyclooxygenase inhibitor indomethacin (50 mu M) was found to attenuate the interleukin-1 beta-induced effects on both long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials. The lipid second messenger analogue C2 ceramide (20 mu M) was found to attenuate the expression of long-term potentiation (108 +/- 3% of baseline 1 h following tetanic stimulation), and this effect was not blocked by pre-treatment with SB203580. To investigate a possible role for interleukin-1 beta in the normal expression of long-term potentiation, the interleukin-l receptor antagonist (25 ng/ml) was applied during the maintenance phase of long-term potentiation. This was found to depress the sustained expression of long-term potentiation (116+/-6% of baseline 1 h following tetanic stimulation). Our results indicate possible signalling mechanisms by which interleukin-1 beta at pathophysiological concentrations may serve to inhibit long-term potentiation, and also suggests a role for IL-1 beta in the physiological expression of synaptic plasticity in the rat dentate gyrus in vitro. (C) 1999 IBRO. Published by Elsevier Science Ltd.