Maternal P2X7 receptor inhibition prevents autism-like phenotype in male mouse offspring through the NLRP3-IL-1β pathway

• Published in: Brain, behavior, and immunity Vol. 101; pp. 318 - 332
• Main Authors: Szabó, Dorottya, Tod, Pál, Gölöncsér, Flóra, Román, Viktor, Lendvai, Balázs, Otrokocsi, Lilla, Sperlágh, Beáta
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.03.2022
• Subjects: Animals; Autism; Autistic Disorder - genetics; Behavior; Behavior, Animal; Cytokines; Disease Models, Animal; Female; Infection; Male; Maternal immune activation; Mice; Neurodevelopment; Neuroinflammation; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; P2X7; Phenotype; Poly(I:C); Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Purinergic P2X7 - genetics; Infection; Autism; Maternal immune activation; Cytokines; P2X7; Poly(I:C); Neurodevelopment; Neuroinflammation; Behavior
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2022.01.015

•Maternal NLRP3 antagonist treatment counteracts autistm-like phenotype in offspring.•Maternal immune activation triggers P2X7-dependent IL-1β production.•Time-dependent induction of immune mediators following maternal immune activation.•Repeated P2X7 antagonist treatment reduces autism-like behavior in adult offspring. Autism spectrum disorder (ASD) is a complex neurodevelopmental condition caused by interactions of environmental and genetic factors. Recently we showed that activation of the purinergic P2X7 receptors is necessary and sufficient to convert maternal immune activation (MIA) to ASD-like features in male offspring mice. Our aim was to further substantiate these findings and identify downstream signaling pathways coupled to P2X7 upon MIA. Maternal treatment with the NLRP3 antagonist MCC950 and a neutralising IL-1β antibody during pregnancy counteracted the development of autistic characteristics in offspring mice. We also explored time-dependent changes of a widespread cytokine and chemokine profile in maternal blood and fetal brain samples of poly(I:C)/saline-treated dams. MIA-induced increases in plasma IL-1β, RANTES, MCP-1, and fetal brain IL-1β, IL-2, IL-6, MCP-1 concentrations are regulated by the P2X7/NLRP3 pathway. Offspring treatment with the selective P2X7 receptor antagonist JNJ47965567 was effective in the prevention of autism-like behavior in mice using a repeated dosing protocol. Our results highlight that in addition to P2X7, NLRP3, as well as inflammatory cytokines, may also be potential biomarkers and therapeutic targets of social deficits and repetitive behaviors observed in autism spectrum disorder.