Toxoplasma gondii infection and chronic IL-1 elevation drive hippocampal DNA double-strand break signaling, leading to cognitive deficits

Authors:

Marcy Belloy, Benjamin A. M. Schmitt, Florent H. Marty, Charlotte Paut, Emilie Bassot, Amel Aïda, Marine Alis, Margot Zahm, Adeline Chaubet, Hugo Garnier, Thelma Flores-Aguilar, Elisa Roitg, Renzo Gutierrez-Loli, Sophie Allart, Romain Ecalard, Raphaël Boursereau, Gaëtan Ligat, Daniel Gonzalez-Dunia, Nicolas Blanchard, Elsa Suberbielle

Keywords:

Chronic inflammation; cytokines; interleukin-1; cognitive impairment; Toxoplasma gondii

Abstract:

Chronic inflammation, resulting from infections, is characterized by increased levels of cytokines including interleukin-1 (IL-1), but little is known about how IL-1 contributes to cognitive impairment, potentially via epigenetic processes. Here we demonstrate that mice chronically infected with the parasite Toxoplasma gondii exhibit impaired spatial memory, which is dependent on neuronal IL-1 signaling and mimicked by chronic exposure to IL-1β. Both T. gondii infection and chronic IL-1β drive H2A.X-dependent DNA double-strand break signaling in hippocampal neurons and invalidating neuronal H2A.X-dependent signaling blocks memory impairments caused by either exposure. Our results highlight the instrumental role of cytokine-induced double-strand-break-dependent signaling in spatial memory defects, which may be relevant to multiple brain diseases.

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