Social deficits in mice prenatally exposed to valproic acid are intergenerationally inherited and rescued by social enrichment.

Intergenerational transmission of the effects of environmental factors on brain function and behavior can occur through epigenetic mechanisms. Valproic acid (VPA) is an anticonvulsant drug that, when administered during pregnancy, causes various birth defects. The mechanisms of action are largely unclear: VPA can reduce neuronal excitability, but it also inhibits the histone deacetylases, affecting gene expression. Here we evaluated whether the effects of valproic acid prenatal exposure on autism spectrum disorder (ASD)-related behavioral phenotypes can be transmitted to the second generation (F2) through the paternal or the maternal lineage. Indeed, we found that F2 males of the VPA pedigree show reduced sociability, which can be rescued by exposing the animals to social enrichment. Moreover, as is the case for F1 males, F2 VPA males show increased c-Fos expression in the piriform cortex. However, F3 males show normal sociability, indicating that VPA's effects on this behavior are not transgenerationally inherited. Female behavior is not affected by VPA exposure, and we found no evidence of maternal transmission of the consequences of this pharmacological treatment. Finally, all animals exposed to VPA and their descendants show reduced body weight, highlighting an intriguing effect of this compound on metabolism. We propose the VPA model of ASD as a valuable mouse model to study the role of epigenetic inheritance and its underlying mechanisms affecting behavior and neuronal function.

Early estradiol exposure masculinizes disease-relevant behaviors in female mice.

Most psychiatric disorders show a sex bias in incidence, symptomatology, and/or response to treatment. Males are more susceptible to neurodevelopmental disorders including autism spectrum disorder and attention-deficit activity disorder, while women are more prone to major depressive disorder and anxiety disorders after puberty. A striking difference between males and females in humans and other mammals is that males undergo a process of brain masculinization due to the early exposure to gonadal hormones. In rodents, this developmental organization of the brain is essential for adult males to express the appropriate sexual behaviors in the presence of a receptive female. Our goal was to determine whether this process of brain masculinization influences behaviors relevant to psychiatric disorders. To this aim, we studied sex differences and the effect of neonatal 17ß-estradiol benzoate treatment of female mice on different disease-relevant behaviors. Our analysis includes postnatal behavior, juvenile play, and adult tests for sociability, repetitive behaviors, anxiety, and depression. Our results show that the sex differences observed in exploration, repetitive behaviors, and depression-related behaviors are largely reduced when females are neonatally treated with 17ß-estradiol benzoate. These results suggest a role of neonatal sex steroids in the development of disease-relevant behaviors and provide evidence supporting a role for perinatal exposure to estrogens and androgens on the development and manifestation of psychiatric disorders.