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

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-1beta. Both T. gondii infection and chronic IL-1beta 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. Overall design: Commercial C57BL/6 male mice were acclimated for one week in the experimental BSL2 facility, prior to intraperitoneal (i.p.) injection with 200 Pru-derived tachyzoites (Pru.SAG1-OVA leading to encephalitis, or Pru.GRA6-OVAleading to latency) in 200 µL of PBS, or with 200 µL of PBS only for the uninfected group.