Gender specific neurobehavioral and gene expression changes in a valproic acid (VPA)–induced mouse model of autistic like behavior and correction by S-adenosylmethionine (SAMe)

In the last 20years, there has been a gradual rise in the prevalence of autistic-like behavior (ASD) as well as of other neurodevelopmental disorders. The etiology of ASD is genetic, environmental, and epigenetic. There are distinct clinical and pathophysiological differences between genders. Valproic acid (VPA) is a known teratogenic anticonvulsant that is a histone deacetylase inhibitor. Following prenatal or early postnatal administration, VPA may also induce autistic-like behavior in rodents. We injected a single dose of VPA either prenatally or early postnatally to ICR mice and induced ASD-like behavior. Concomitant administration of SAMe alleviated the ASD-like behavior and corrected most of the changes in gene expression induced by VPA. The behavioral and molecular changes differed between male and female mice in both experimental settings, thus mimicking the human situation. We conclude that both VPA and SAMe are powerful and antagonistic epigenetic modifiers.