title: A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning.
abstract: We have previously shown that long-term potentiation (LTP) induces hippocampal IL-1β 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-1β and IL-6, also IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNFα 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 TNFα 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.
authors.affiliation: Research Group Immunophysiology, Institute of Physiology and Pathophysiology, Philipps University, 35037 Marburg, Germany.
authors.forename: Adriana
authors.initials: A
authors.lastname: del Rey
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
authors.forename: Wolfram
authors.initials: W
authors.lastname: Wetzel
authors.forename: Anke
authors.initials: A
authors.lastname: Randolf
authors.forename: Hugo O
authors.initials: HO
authors.lastname: Besedovsky
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D018891:Dentate Gyrus / Q000276:immunology*; D057809:HEK293 Cells; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; C088601:NR2E1 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha
keywords: Brain-borne cytokine network; Learning; Long term potentiation; Memory consolidation; Synaptic plasticity