Autism spectrum disorder

Previously we showed that activation of the purinergic P2X7 has a role in the conversion of maternal immune activation (MIA) to ASD-like features in 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 neutralizing 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, and MCP-1 concentrations have been shown to be the effect of P2X7/NLRP3 regulation. 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 repetitive behavioral and social deficits observed in autism spectrum disorder. In the future, we plan to gain a better understanding of the signaling mechanisms, as well as the pathomechanism of sex differences in the development of such pervasive disorders and to identify new potential aetiological factors.