The Inhibitory Effects of Interleukin‐6 on Synaptic Plasticity in the Rat Hippocampus Are Associated with an Inhibition of Mitogen‐Activated Protein Kinase ERK

Abstract

Several cytokines have short-term effects on synaptic transmission and plasticity that are thought to be mediated by the activation of intracellular protein kinases. We have studied the effects of interleukin-6 (IL-6) on the expression of paired pulse facilitation (PPF), posttetanic potentiation (PTP), and long-term potentiation (LTP) in the CA1 region of the hippocampus as well as on the activation of the signal transducer and activator of transcription-3 (STAT3), the mitogen-activated protein kinase ERK (MAPK/ERK), and the stress-activated protein kinase/c-Jun NH 2 -terminal kinase (SAPK/JNK). IL-6 induced a marked and dose-dependent decrease in the expression of PTP and LTP that could be counteracted by the simultaneous treatment with the tyrosine kinase inhibitor lavendustin A (LavA) but did not significantly affect PPF. The IL-6-induced inhibition of PTP and LTP was accompanied by a simulation of STAT3 tyrosine phosphorylation and an inhibition of MAPK/ERK dual phosphorylation, in the absence of changes in the state of activation of SAPK/JNK. Both effects of IL-6 on STAT3 and MAPK/ERK activation were effectively counteracted by LavA treatment. The results indicate that tyrosine kinases and MAPK/ERK are involved in hippocampal synaptic plasticity and may represent preferential intracellular targets for the actions of IL-6 in the adult nervous system. Key Words: Long-term potentiation-Posttetanic potentiation-Tyrosine phosphorylation-Mitogenactivated protein kinase -Signal transducer and activator of transcription-3 (STAT3). J. Neurochem. 75, 634 -643 (2000).The molecular mechanisms underlying changes in synaptic efficacy are beginning to be elucidated and, in most cases, involve long-lasting changes at both pre-and postsynaptic levels mediated by the activation of intracellular signal transduction systems as well as by changes in gene expression. There is increasing evidence that protein kinases such as protein kinase C, Ca 2ϩ / calmodulin-dependent protein kinase II, protein kinase A, Src-family protein kinases, and the mitogen-activated protein kinase ERK (MAPK/ERK) are intimately involved in the expression of long-term potentiation (LTP) in the hippocampus (Grant et al

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“…In this regard, it is important to note that although some groups have reported neuronal expression of most TLRs both in vitro and in vivo (36,37), others have been unable to demonstrate expression of TLR2 on neurons (38). The implication of this finding for the present study is that the mechanism underlying the Pam 3 Csk 4 -induced depression in LTP may result from its ability to release IL-1␤, IL-6, and TNF␣ from glia; each of these inflammatory cytokines has been shown to inhibit LTP (17,39,40).…”

Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults

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