Inhibition of LTP-induced translation by IL-1β reduces the level of newly synthesized proteins in hippocampal dendrites.

In rodent hippocampus, the inflammatory cytokine interleukin-1β (IL-1β) impairs memory and long-term potentiation (LTP), a major form of plasticity that depends on protein synthesis. A better understanding of the mechanisms by which IL-1β impairs LTP may help identify targets for preventing cognitive deterioration. We tested whether IL-1β inhibits protein synthesis in hippocampal neuron cultures following chemically-induced LTP (cLTP). Fluorescent-tagging using click-chemistry showed that IL-1β reduces the level of newly synthesized proteins in proximal dendrites of cLTP stimulated neurons. Relative to controls, in cLTP stimulated neurons IL-1β inhibited Akt/mTOR signaling, as well as the upregulation of GluA1, an AMPA receptor subunit, and LIMK1, a kinase that promotes actin polymerization. Notably, a novel TIR domain peptidomimetic (EM163) blocked both the activation of p38 and the suppression of cLTP-dependent protein synthesis by IL-1β. Our data support a model where IL-1β suppresses LTP directly in neurons by inhibiting mTOR-dependent translation.