Dr. Marcy Belloy (Toulouse / FR), Dr. Benjamin Schmitt (Toulouse / FR), Dr. Florent Marty (Toulouse / FR), Charlotte Paut (Toulouse / FR), Emilie Bassot-Parra (Toulouse / FR), Amel Aïda (Toulouse / FR), Marine Alis (Toulouse / FR), Romain Ecalard (Toulouse / FR), Dr. Raphaël Boursereau (Toulouse / FR), Dr. Daniel Gonzalez-Dunia (Toulouse / FR), Professor Nicolas Blanchard (Toulouse / FR), Dr. Elsa Suberbielle (Toulouse / FR)
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-1β 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-1β. 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.