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-fEPSPs 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-1 type 1 receptors. This ability of IL-1ra 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-1ra 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.
Curran
B
B
Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, National University of Ireland, Dublin.
O'Connor
J J
JJ
D000818:Animals; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18 / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C507763:IL1RN protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha