A cytokine network in the brain during synaptic plasticity and learning

Our previous studies have shown, in vivo and in vitro , that long-term potentiation (LTP) induces an NMDA receptor-dependent expression of IL-1β and IL-6 in the hippocampus. Blockade of the receptors for these cytokines either decreases (IL-1) or supports (IL-6) LTP maintenance, indicating the physiological relevance of their effects. Consistently, interference with IL-1 or IL-6 signalling also restricts or favours, respectively, hippocampus-dependent learning. The question that arises is whether brain-borne cytokines that interact with each other affect learning and memory consolidation just because they have a tonic, permissive effect or because their production increases during learning and are therefore part of the neuro-chemical changes involved in this process, as it occurs during LTP. Here we provide evidence that, besides IL-1β and IL-6, the endogenous IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNF α , are produced during LTP in freely moving rats. Furthermore, we found that IL-1β and IL-6 genes are over-expressed in different hippocampal regions soon after learning a hippocampus-dependent alternation task. Restricted changes in IL-18 and no differences in TNF α and IL1-ra expression were noticed in the hippocampus during this learning process, but IL-1ra transcripts were significantly reduced in the prefrontal cortex. These effects were not noticed in pseudo-trained rats that could not learn the task. Taken together with previous studies, we conclude that activation of a cytokine network in the brain is a physiologic relevant condition not only for LTP maintenance but also for the consolidation of the learning process.