Sex-specific effects of prenatal VPA exposure on behavior and neuroinflammation

DEPINO AM; KAZLAUSKAS N; SEIFFE A; CAMPOLONGO M; ZAPPALA C

Daegu

Congreso; 10th International Brain Research Organization (IBRO) World Congress of Neuroscience; 2019

International Brain Research Organization

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an incidence three 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 saline at gestational day 12.5. Their male and female offspring were evaluated in a social interaction test at adulthood, and only male VPA mice showed reduced sociability levels and a lack of social preference. We then analyzed the hypothalamus-pituitary-adrenal (HPA) response and the neuroinflammatory state in adult and young animals. Adult VPA males exhibited increased basal corticosterone levels, while VPA females showed levels comparable to controls. As male mice showed a blunted HPA activation at PD21 when compared to female mice, we propose that this early dimorphism could explain the different effects of VPA on HPA function. In addition, prenatal VPA exposure resulted in altered astroglial and microglial cell density levels in the dentate gyrus and the cerebellum in adult mice. These neuroinflammatory effects were more pronounced in female than male mice, and appeared at early developmental stages. We propose that these postnatal glial density differences could underlie the behavioral differences observed in adulthood, when only males show a social deficit.We consider that our work contributes to the understanding of biological mechanisms affected by VPA on male and female rodents, and to shed light on the study of possible resilience mechanisms in the female population and/or susceptibility to ASD in boys.