Female mice postnatally exposed to estradiol show altered autism-related behaviors

SEIFFE A; RAMIREZ MF; DI GUARDIA CASELLA LM; BARRIOS C; ALBARRAN MM; DEPINO AM

Chicago

Congreso; Neuroscience 2021 50th Annual Meeting of the Society for Neuroscience; 2021

Society for Neuroscience

Autism spectrum disorders (ASD) are characterized by reduced sociability, diminished communicative skills and repetitive behaviors. Notably, the proportion between boys and girls diagnosed with ASD is about 4 to 1. A striking difference between males and females in humans and other mammals is that males suffer a process of brain masculinization, due to the early exposure to gonadal hormones. In rodents, this developmental organization of the brain is essential for the proper display of sexual behaviors in adulthood, but it also determines other sex differences in brain function and behavior.Our first aim was to evaluate whether this process of brain masculinization influences the performance in behaviors relevant to ASD. To this aim, we studied sex differences and the effect of neonatal 17β-estradiol benzoate (E2) treatment of female mice (CF1 outbred) on different ASD-relevant behaviors. On postnatal days (PND) 2, 5 and 8, female pups were injected (s.c.) with estradiol (50 µg; E2, n = 19) or vehicle (OIL, n = 12). On adulthood (from PND60), we found that the sex differences observed in exploration (distance in the Y maze, one-way ANOVA p = 0.001; and open field, one-way ANOVA p = 0.014), repetitive behaviors (self-grooming, one-way ANOVA p = 0.020), and depression-related behaviors (immobility in the forced swim test, one-way ANOVA, p = 0.004) are largely reduced when females are neonatally treated with E2.Recently, we observed that the prenatal exposure at gestational day 12.5 to 600 mg/kg valproic acid (VPA) results in decreased sociability of male offspring, while female littermates express normal levels of social interaction. Our second aim was then to identify the biological mechanisms involved in this differential impact of VPA in male and female mice. Our hypothesis is that brain masculinization is necessary for prenatal VPA exposure to affect autism-related behaviors, neuronal alterations and gliosis. To test this hypothesis, we studied the effect of postnatal exposure to E2 in female mice of the VPA model of autism, analyzing four experimental groups: SAL-OIL (n = 13), SAL-E2 (n = 17), VPA-OIL (n = 12) and VPA-E2 (n = 14). Our results show that VPA-E2 females present no habituation to the stimulus mouse throughout the four consecutive presentations (three-way ANOVA followed by Fisher?s LSD test, presentation 1 vs 4 p > 0.05), while the other three experimental groups show significative habituation (p < 0.05). These results demonstrate that the combination of prenatal VPA exposure and postnatal E2 treatment results in altered sociability in female mice. However, all animals spent a similar amount of time in self-grooming (two-way ANOVA p > 0.05), suggesting that repetitive behaviors are not altered but these pharmacological treatments.Further studies of the VPA-E2 mice could help us identify possible biological mechanisms underlying the higher incidence of ASD observed in boys.