Chronic IL-1-induced DNA double-strand break response in hippocampal neurons drives cognitive deficits

Chronic inflammation characterized by increased cytokine levels, such as interleukin-1 (IL-1), accompanies many neurological diseases but little is known about IL-1 contribution to cognitive impairment and its interplay with epigenetic processes, including the DNA double-strand break (DSB) response. Here, we demonstrate that H2A.X-dependent DSB signaling in hippocampal neurons drives cognitive deficits upon chronically elevated IL-1. Mice persistently and latently infected with Toxoplasma gondii display impaired spatial memory consolidation along with elevated IL-1{beta} in the hippocampus. We find that neuronal IL-1 signaling in excitatory neurons is required for the spatial memory deficits caused by T. gondii infection and by chronic systemic infusion of IL-1{beta}. In both cases, the deficit in spatial memory was prevented by the abrogation of neuronal H2A.X-dependent signaling. Our results highlight the instrumental role of cytokine-induced DSB-dependent signaling in spatial memory defects. This novel pathological mechanism in inflammation control of neuronal function may extend to several neurological diseases.