Prenatal stress and fluoxetine exposure in BTBR and B6 mice differentially affects autism-like behaviors in adult male and female offspring

Autism spectrum disorder (ASD) is characterized by significant heterogeneity in the variety and severity of symptoms. Prenatal stress and/or exposure to antidepressants may be major contributors to ASD heterogeneity. To date, the effects of prenatal stress or selective serotonin reuptake inhibitor exposure have been primarily examined in common laboratory rat and mouse strains as opposed to in rodent models of autism. The present experiments determined in the BTBR mouse model of autism whether restraint stress (30 min session every 2 days during G4 - G18) and/or exposure to the SSRI, fluoxetine (3 mg/kg during G8 - G18) affects repetitive motor behaviors, anxiety and/or behavioral flexibility in offspring at adulthood. Male and female BTBR mice exhibited elevated grooming behavior compared to that of C57BL/6 J (B6) mice. The prenatal manipulations did not affect grooming in male BTBR mice, but the combination increased rearing and jumping. Prenatal stress, fluoxetine and the combination significantly reduced self-grooming, while concomitantly increasing locomotion in female BTBR mice. These prenatal manipulations also increased rearing and jumping behavior in female BTBR mice. In B6 mice, the prenatal stress conditions increased grooming behavior. In addition, male BTBR mice exposed to prenatal stress and fluoxetine along with female BTBR mice prenatally exposed to fluoxetine were impaired on reversal learning. The prenatal manipulations had no effect on anxiety in either mouse strain. The pattern of results suggest that prenatal exposure to stress and/or a SSRI have long-term effects on autism-like behaviors and may contribute to the heterogeneity and co-morbidity observed in autism.