Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway

Abstract

Studies in humans have revealed that the pathogenesis of autism spectrum disorder (ASD) is linked to white matter abnormalities involving hypomyelination and oligodendroglia dysfunction; however, effective treatments remain limited. Similarly, the valproic acid (VPA) model mice, which are widely used to study ASD, also exhibit white matter abnormalities with hypomyelination. Arecoline has been reported to enhance memory and cognition, facilitate myelination and improve neurological function. This study investigated the therapeutic potential of arecoline in a mouse model of prenatal VPA-induced ASD. We established an ASD mouse model through prenatal exposure to VPA and treated the mice with arecoline for 4 weeks. Behavioral analyses, including the elevated-plus maze, open field, self-grooming, marble-burying, three-chamber, Y-maze, and Morris water maze tests, were conducted to assess the effects of arecoline on behavior. Western blotting was used to detect changes in protein expression in the frontal cortex after arecoline treatment. The results revealed that offspring prenatally exposed to VPA presented characteristic behavioral abnormalities, including increased repetitive and stereotyped behaviors, deficits in social interaction, and impairments in learning and memory, accompanied by reduced expression of the myelin marker MBP and the mature oligodendrocyte marker GST-pi in the frontal cortex. Four-week arecoline treatment (1 and 2 mg/kg/day) significantly ameliorated these behavioral and cognitive abnormalities and restored myelination markers. Further mechanistic investigations demonstrated that arecoline enhanced the phosphorylation levels of AMPKα and CREB in the frontal cortex. This activation upregulated the expression of downstream BDNF, an essential neurotrophic factor for oligodendrocyte maturation and remyelination. These findings suggest that the AMPK/CREB/BDNF pathway may contribute to the therapeutic effects of arecoline, potentially through increased oligodendrocyte maturation and remyelination. This study provides preclinical evidence supporting arecoline as a potential myelination-targeting intervention, with implications for ASD and other neurological disorders involving myelination deficits.

Keywords: AMPK signaling pathway; Arecoline; Autism spectrum disorder; Cognition; Myelination.