Sex-specific effects of prenatal valproic acid exposure on sociability and neuroinflammation: Relevance for susceptibility and resilience in autism

SEIFFE, ARACELI; DEPINO, AMAICHA MARA; CAMPOLONGO, MARCOS; CAMPOLONGO, MARCOS; KAZLAUSKAS, NADIA; ZAPPALA, CECILIA; KAZLAUSKAS, NADIA; ZAPPALA, CECILIA; SEIFFE, ARACELI; DEPINO, AMAICHA MARA

PSYCHONEUROENDOCRINOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2019 vol. 110

0306-4530

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with an incidencefour times higher in boys than in girls. By analyzing the effect of sex in a mouse model of ASD,we were able to identify immune alterations that could underlie this sex bias.Pregnant mice were injected subcutaneously with 600 mg/kg of valproic acid (VPA) or salineat gestational day 12.5. Their male and female offspring were evaluated in a social interactiontest at adulthood, and only male VPA mice showed reduced sociability levels and a lack ofpreference for the social stimulus over a novel object. We then analyzed the corticosterone(CORT) response to an inflammatory stimulus, as a measure of the hypothalamus-pituitaryadrenal(HPA) function, and the neuroinflammatory state in adult and young animals. AdultVPA males exhibited increased basal CORT levels, while VPA females showed levelscomparable to controls. As male mice showed a blunted CORT response at PD21 whencompared to female mice, we propose that this early dimorphism could explain the differenteffects of VPA on HPA function. In addition, prenatal VPA exposure resulted in alteredastroglial and microglial cell density levels in the cerebellum and dentate gyrus of adult mice.These neuroinflammatory effects were more pronounced in females than males, and appearedat early developmental stages. Hence, these postnatal glial density differences could underliethe behavioral alterations observed in adulthood, when only males show a social deficit.Our work contributes to the understanding of biological mechanisms affected by VPA on maleand female rodents and shed light on the study of possible resilience mechanisms in the femalepopulation and/or susceptibility to ASD in boys.