A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning

We have previously shown that long-term potentiation (LTP) induces hippocampal IL-1 beta and IL-6 over-expression, and interfering their signalling either inhibits or supports, respectively, LTP maintenance. Consistently, blockade of endogenous IL-1 or IL-6 restricts or favours hippocampal-dependent memory, effects that were confirmed in genetically manipulated mice. Since cytokines are known for their high degree of mutual crosstalk, here we studied whether a network of cytokines with known neuromodulatory actions is activated during LTP and learning. We found that, besides IL-1 beta and IL-6, also IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNF alpha are over-expressed during LTP maintenance in freely moving rats. The increased expression of these cytokines is causally related to an increase in synaptic strength since it was abrogated when LTP was interfered by blockade of NMDA-glutamate receptors. Likewise, IL-1 and IL-6 were found to be over-expressed in defined regions of the hippocampus during learning a hippocampus-dependent task. However, during learning, changes in IL-18 were restricted to the dorsal hippocampus, and no differences in TNF alpha and IL1-ra expression were noticed in the hippocampus. Noticeably, IL-1ra transcripts were significantly reduced in the prefrontal cortex. The relation between cytokine expression and learning was causal because such changes were not observed in animals from a pseudo-trained group that was subject to the same manipulation but 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 phenomenon not only for LTP maintenance but also for certain types of learning. (c) 2013 Elsevier Inc. All rights reserved.