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 beside the sickness behavior syndrome, 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 in the hippocampus. We find that neuronal IL-1 signaling in excitatory neurons is required for the spatial memory deficit caused by both T. gondii infection and chronic systemic infusion of IL-1β. The abrogation of neuronal H2A.X-dependent signaling simultaneously normalized the pathological transcriptional signatures imprinted by IL-1 in hippocampal neurons and prevented the spatial memory deficit. 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. Chronic inflammation characterized by increased cytokine levels, such as interleukin-1 (IL-1), accompanies many neurological diseases but beside the sickness behavior syndrome, 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 in the hippocampus. We find that neuronal IL-1 signaling in excitatory neurons is required for the spatial memory deficit caused by both T. gondii infection and chronic systemic infusion of IL-1β. The abrogation of neuronal H2A.X-dependent signaling simultaneously normalized the pathological transcriptional signatures imprinted by IL-1 in hippocampal neurons and prevented the spatial memory deficit. 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. 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.