Valproic acid exposure decreases the mRNA stability of Bcl-2 via up-regulating miR-34a in the cerebellum of rat

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, limited verbal communication and repetitive behaviors. Previous studies have shown that the level of Bcl-2 in the brain tissues of ASD patients is significantly decreased. However, the mechanisms underlie the down-regulation of Bcl-2 in ASD is still unknown. In this study, we investigated the alteration of Bcl-2 level and associated mechanisms in valproic acid (VPA) exposed ASD rats. VPA exposure resulted in ASD-like behaviors in rats, such as repetitive behavior and social interaction impairment. VPA exposure also down-regulated the expression of Bcl-2 both at mRNA and protein levels, either in cerebellar cortex or primary cerebellar cortical neuronal cells. Furthermore, VPA treatment decreased the mRNA stability of Bcl-2 instead of down-regulating its transcriptional activity. Meanwhile, VPA exposure up-regulated the expression of miR-34a in cerebellar cortex and primary cerebellar cortical neuronal cells. The mimics of miR-34a directly inhibited the expression of Bcl-2 and its antagonist blocked the down-regulation effect of VPA on Bcl-2 in primary cerebellar cortical neuronal cells. Our study implies that VPA may influence ASD through sequential up-regulating miR-34a and therefore down-regulating Bcl-2 in the brain tissues of rats.