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: 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) ß-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.