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. H2axfl/flCre- (neuronWT) or H2axfl/flCre+ (neuronKO) were implanted with osmotic minipumps containing saline or IL-1beta solutions for 35 days. Hippocampi were microdissected and pooled from 2 mice of the same condition. Neuronal nuclei from pooled hippocampi were isolated by FANS as described in Fernandez-Albert et al. (PMID 31501571). After sorting, neuronal nuclei were centrifuged at 1000 g for 7 min at 4°C and pellet was resuspended in RLT buffer (Qiagen) supplemented with 1% (vol/vol) β-mercaptoethanol (final concentration 143mM, Sigma). Samples were homogenized through QiaShredder columns (Qiagen) and stored at -80°C until processing. Bulk nuclear RNA extraction was performed using RNeasy Micro Kit (Qiagen) following manufacturer’s instructions.