title: Altered peripheral and central inflammatory responses in a mouse model of autism.
abstract: Increasing clinical and experimental evidence links immune and inflammatory alterations with the pathogenesis of autism spectrum disorders (ASD). Autistic individuals show signs of neuroinflammation, altered inflammatory responses, and immune abnormalities throughout life. Mice injected subcutaneously with 600 mg/kg valproic acid (VPA600) at gestational day 12.5 show reduced social interaction in adulthood (at 8 weeks of age), and they have been proposed as a mouse model of autism. Here, we show that these adult animals present signs of chronic glial activation in the hippocampus and the cerebellum. Moreover, when they are challenged with a peripheral inflammatory stimulus (intraperitoneal lipopolysaccharides, LPS), VPA600 animals show an exacerbated inflammatory response. Two hours after LPS injection, VPA600 animals secrete more corticosterone to the blood than control mice, and show an increase in the levels of expression of proinflammatory cytokines in the spleen. After LPS challenge, VPA600 mice also show signs of increased neuroinflammation compared with control mice: they have more microglial cells in the hippocampus, and they show higher levels of proinflammatory cytokines in the cerebellum. Our results provide evidence of basal neuroinflammation and an altered inflammatory response in the VPA model of autism. We propose that this model can be used to evaluate the contribution of inflammatory reactivity to autism-related behaviors. These studies will contribute to elucidate the role of the inflammatory alterations observed in ASD individuals.
authors.affiliation: Institute for Physiology, Molecular Biology and Neurosciences, CONICET-UBA, Buenos Aires, Argentina; Department of Physiology, Molecular and Cellular Biology, FCEyN, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Luciana
authors.initials: L
authors.lastname: Lucchina
authors.forename: Amaicha Mara
authors.initials: AM
authors.lastname: Depino
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000276:immunology*; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced / Q000276:immunology*; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood; D005260:Female; D006624:Hippocampus / Q000276:immunology*; D018836:Inflammation Mediators / Q000097:blood*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008957:Models, Genetic; D009457:Neuroglia / Q000276:immunology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D060888:Real-Time Polymerase Chain Reaction; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014635:Valproic Acid; D003345:Corticosterone
keywords: astroglia; behavior; cytokines; hypothalamus-pituitary-adrenal axis; microglia; valproic acid