Anales RANF

P.44 NLRP3 INFLAMMASOME PATHWAY MEDIATES THE EFFECT P2X7 RECEPTOR ACTIVATION IN THE MATERNAL IMMUNE ACTIVATION MODEL OF AUTISM Szabó Dorottya, Otrokocsi Lilla, Sperlágh Beáta Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. Autism spectrum disorder (ASD) is a complex neurodevelopmental condition caused by interactions of environmental and genetic factors. We have recently shown that the activation of P2X7 receptors elicit ASD-like offspring phenotype in the maternal immune activation (MIA) model of ASD in mice. The NLRP3 inflammasome assembly is an important downstream signalling pathway mediating the effect of P2X7 receptor activation. Because MIA lead to the induction of pro-inflammatory cytokine response with the participation of P2X7 receptors and cytokines can compromise fetal brain development, the aim of this study was to clarify the role of the NLRP3 in this process. MIA was induced by poly(I:C) (2 x 3mg/kg i.p) in wild-type and P2rx7 deficient pregnant mouse dams . Before poly(I:C) treatment, mice were injected with the selective NLRP3 inflammasome antagonist ( MCC950, 1x50 mg/kg). We carried out autism relevant behavior tests on young adult male offspring and brain samples were collected for determination of the Purkinje cell density in the lobeVII. of the cerebellum and electronmicroscopic examination of synaptosome integrity. Maternal poly(I:C) treatment elicited social deficit, increase in repetitive behaviors and impairment of sensorimotor coordination. In addition, elevated number of malformed synaptosomes and lowered Purkinje cell density was observed. Administration of MCC950 prevented the development of these autistic features. In P2rx7 deficient mice, poly(I:C) treatment did not induce autistic phenotype. In conclusion, poly(I:C) treatment induced autism-like behavior and morphological changes in the offspring by the activation of P2X7 receptor and with the participation of NLRP3 inflammasome signaling pathway. These results may help to clarify the downstream signalling pathway of P2X7 receptor, thus finding potential pharmacotherapeutic targets of ASD in the future.