The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro

The effects of the pro-inflammatory cytokine interleukin-18 (IL-18) were investigated on both normal and isolated N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory post synaptic potentials (fEPSP) and on the induction of long-term potentiation (LTP) in the rat dentate gyrus in vitro. Bath perfusion with IL-18 (100 ng/ml) for 20 min prior to high-frequency stimulation had no significant effect on baseline synaptic transmission or paired pulse depression, but did impair the induction of LTP (115.7 +/- 8.8% versus 150.8 +/- 8.1% in vehicle control slices, n=6, P <0.05 at 60 min). Further analysis demonstrated that IL-18 significantly depressed the amplitude of pharmacologically isolated NMDA receptor-mediated fEPSP (NMDA-fEPSP 77.4 +/- 4.3% of baseline compared to controls at 1 h, P <0.05, n=7), an effect that may underlie the impairment of LTP by IL-18. This action of IL-18 on LTP and NMDA-fFPSPs was attenuated in full by pretreatment of slices with exogenously applied IL-1 receptor antagonist (IL-1ra, 100 ng/ml), the naturally occurring antagonist of IL-I type I receptors. This ability of IL-Ira to block the inhibitory effects of IL-18 is likely to be receptor-specific as no reversal of the tumour necrosis factor-alpha -induced inhibition of LTP was seen with IL-Ira administration (110.7 +/- 5.4% versus tumour necrosis factor-alpha -treated slices; 107.4 +/- 8.7%, P=0.6, n=6). These are the first experiments providing, evidence of a direct neuromodulatory role for IL-18 in synaptic plasticity. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.