Adenosine: a Mediator of Interleukin-1β-Induced Hippocampal Synaptic Inhibition

Abstract

Interleukin-1 (IL-1) is a pleotrophic cytokine implicated in a variety of central activities, including fever, sleep, ischemic injury, and neuromodulatory responses, such as neuroimmune, and neuroendocrine interactions. Although accumulating evidence is available regarding the expression pattern of this cytokine, its receptors in the CNS, and its mechanistic profile under pathological levels, it is unclear whether this substance modulates central neurons under physiological concentrations. Further, in light of the functional and spatial overlap between the adenosine and IL-1 systems, it is not known whether these two systems are coupled. We report here that, in rat brain slices, brief application of sub-femtomolar IL-1beta causes a profound decrease of glutamate transmission, but not GABAergic inhibition, in hippocampal CA1 pyramidal neurons. This decrease by IL-1beta is prevented by pharmacological blockade of adenosine A1 receptors. In addition, we show that IL-1beta failed to suppress glutamate transmission at room temperature. Because the production and release of adenosine in the CNS is thought to be metabolically dependent, this observation suggests that one of the functions of IL-1beta is to increase the endogenous production of adenosine. Together, these data suggest for the first time that sub-femtomolar levels of IL-1 can effectively modulate glutamate excitation in hippocampal neurons via an adenosine-dependent mechanism.

Competitive interactions between endogenous LTD and LTP in the hippocampus underlie the storage of emotional memories and stress-induced amnesia

“…Finally, and perhaps most relevant to the endogenous LTD issue, Ikegaya et al (2003) reported that IL-1b administration rapidly produced an LTD-like suppression of synaptic transmission in CA1, in vitro. Thus, the basis of the LTD-like effects observed by Garcia et al (1998b), as well as the novelty-induced depotentiation of LTP (Xu et al, 1998a;Manahan-Vaughan and Braunewell, 1999;Abraham et al, 2002;Straube et al, 2003;Kemp and Manahan-Vaughan, 2004) may involve an IL-1b-mediated reduction of glutamate release and enhancement of adenosinemediated inhibition in the hippocampus (Murray et al, 1997;Luk et al, 1999;Kelly et al, 2003).…”

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…56,65,66 As described below, these and other inflammatory cytokines can act as somnogens, indicating a major but incompletely understood connection between the immune system and sleep. 4,16,29,31,36,[67][68][69][70][71][72][73][74][75][76][77][78][79] Another potent endogenous somnogen is the PGD 2 prostaglandin, which preferentially induces NREM sleep. 11,28,80,81 The somnogenic activity of PGD 2 is mediated at least in part by the ability of brain-produced PGD 2 to increase the concentration of extracellular adenosine.…”

Interleukin (IL)‐1β, IL‐1 receptor antagonist, IL‐6, IL‐8, IL‐10, and tumor necrosis factor α gene polymorphisms in patients with febrile seizures

“…GABA terminals are abundant in areas containing thermosensitive neurons, and muscimol application causes reductions in both firing rate and thermo-sensitivity. IL-1b and other cytokines have been shown to influence signaling with many neurotransmitters, including norepinephrine, serotonin, GABA, acetylcholine, and adenosine (14,15). The balance between these cytokines influences the level of fever and could therefore play a role in the pathogenesis of FSs.…”