Loss of interleukin 1 signaling causes impairment of microglia- mediated synapse elimination and autistic-like behaviour in mice

• Published in: Brain, behavior, and immunity behavior, and immunity, 2024-03, Vol.117, p.493-509
• Main Authors: Borreca, Antonella, Mantovani, Cristina, Desiato, Genni, Corradini, Irene, Filipello, Fabia, Elia, Chiara Adriana, D'Autilia, Francesca, Santamaria, Giulia, Garlanda, Cecilia, Morini, Raffaella, Pozzi, Davide, Matteoli, Michela
• Format: Article
• Language: English
• Subjects: Autism spectrum disorder (ASD); IL-1 signaling; Interleukin-1 Receptor antagonist (IL-1Ra); Microglia; mTOR signaling; Neurodevelopmental disorders; Proinflammatory cytokines; Rapamycin treatment; Synapse engulfment; Synaptic density
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2024.01.221

[Display omitted] •Il1r1-/- mice show ASD - like behaviors and impaired synapse engulfment b y microglia•T he microglial defect in Il1r1-/- mice is linked to activation of the mTOR pathway.•Treatment with rapamycin restores microglial function and improves behavioral defects.•Our data suggest that IL-1R1 plays a role in microglial - mediated synapse refinement.•We provide insights into the mechanisms underlying neurodevelopmental disorders. In the last years, the hypothesis that elevated levels of proinflammatory cytokines contribute to the pathogenesis of neurodevelopmental diseases has gained popularity. IL-1 is one of the main cytokines found to be elevated in Autism spectrum disorder (ASD), a complex neurodevelopmental condition characterized by defects in social communication and cognitive impairments. In this study, we demonstrate that mice lacking IL-1 signaling display autistic-like defects associated with an excessive number of synapses. We also show that microglia lacking IL-1 signaling at early neurodevelopmental stages are unable to properly perform the process of synapse engulfment and display excessive activation of mammalian target of rapamycin (mTOR) signaling. Notably, even the acute inhibition of IL-1R1 by IL-1Ra is sufficient to enhance mTOR signaling and reduce synaptosome phagocytosis in WT microglia. Finally, we demonstrate that rapamycin treatment rescues the defects in IL-1R deficient mice. These data unveil an exclusive role of microglial IL-1 in synapse refinement via mTOR signaling and indicate a novel mechanism possibly involved in neurodevelopmental disorders associated with defects in the IL-1 pathway.