Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus

In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1 beta (IL-1 beta). In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1 beta impairment. In hippocampal neuronal cultures, IL-1 beta increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1 beta. To evaluate whether synapses develop a similar heightened sensitivity to IL-1 beta with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1 beta impairs LTP directly at the synapse and that sensitivity to IL-1 beta is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1 beta was due to IL-1 receptor subunit reconfiguration, characterized by a shift in the AcP/AcPb ratio, paralleling our culture data. We suggest that the age-related increase in brain IL-1 beta levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1 beta. Accordingly, selective blocking of AcP-dependent signaling with Toll-IL-1 receptor domain peptidomimetics prevented IL-1 beta-mediated LTP suppression and blocked the memory impairment induced in aged mice by peripheral immune challenge (bacterial lipopolysaccharide). Overall, this study demonstrates that increased AcP signaling, specifically at the synapse, underlies the augmented vulnerability to cognitive impairment by IL-1 beta that occurs with age.