Prenatal 4-phenylbutyric acid administration during mid-gestation ameliorates ASD-like behaviors by reducing cortical endoplasmic reticulum stress in VPA-induced ICR and BTBR mouse models.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive behaviors. Increasing evidence suggests that endoplasmic reticulum (ER) stress contributes to abnormal brain development in ASD; however, whether prenatal modulation of ER stress can prevent ASD-like phenotypes remains unclear. In this study, we investigated the effects of prenatal administration of the chemical chaperone 4-phenylbutyric acid (4-PBA) in two etiologically distinct ASD mouse models: valproic acid (VPA)-exposed Jcl:ICR (ICR) mice and BTBR T+ Itpr3tf /J (BTBR) mice. Social behaviors were evaluated using the three-chamber test, and repetitive behaviors were assessed by self-grooming duration. 4-PBA was administered to mid-gestation mice, and behavioral changes in the male offspring derived-two type ASD model (VPA and BTBR mice) were evaluated. 4-PBA reduced ER stress in the cerebral cortex of the offspring male VPA and BTBR mice. In particular, 4-PBA strongly inhibited the expression of 94-kDa glucose-regulated protein, an ER stress marker, in BTBR male mice. In addition, 4-PBA improved synaptic organizer expression and neuronal maturation, which are diminished in ASD, specifically in the cerebral cortex of VPA mice. Furthermore, 4-PBA improved social reciprocity, a behavior specific to ASD in male VPA and BTBR mice. In conclusion, ER stress during mid-pregnancy is strongly associated with the development of ASD symptoms. Furthermore, the reduction in ER stress by 4-PBA leads to the suppression of ASD symptoms. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a lack of sociality, and the difficulty in forming social relationships often leads to various social problems. Prenatal administration of 4-PBA to mothers may reduce the risk of developing ASD, and we believe this could be a new approach to prevention.