The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy

• Published in: Scientific reports Vol. 6; no. 1; p. 36250
• Main Authors: Choi, Chang Soon, Gonzales, Edson Luck, Kim, Ki Chan, Yang, Sung Min, Kim, Ji-Woon, Mabunga, Darine Froy, Cheong, Jae Hoon, Han, Seol-Heui, Bahn, Geon Ho, Shin, Chan Young
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.11.2016; Nature Publishing Group
• Subjects: 631/378/1689/1373; 631/378/2584/2585; 631/378/3919; 64; 64/60; Animals; Anxiety; Autism; Autism Spectrum Disorder - chemically induced; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - physiopathology; Behavior, Animal - drug effects; Developmental disabilities; Environmental factors; Epigenetics; Female; Frontal Lobe - metabolism; Frontal Lobe - physiopathology; Heredity; Humanities and Social Sciences; Hyperactivity; Male; Maternal Exposure - adverse effects; Mice; Mice, Inbred ICR; multidisciplinary; Pregnancy; Science; Seizures; Valproic acid; Valproic Acid - adverse effects; Valproic Acid - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep36250

Autism spectrum disorder (ASD) is a heterogeneously pervasive developmental disorder in which various genetic and environmental factors are believed to underlie its development. Recently, epigenetics has been suggested as a novel concept for ASD aetiology with a proposition that epigenetic marks can be transgenerationally inherited. Based on this assumption of epigenetics, we investigated the transgenerational inheritance of ASD-like behaviours and their related synaptic changes in the VPA animal model of ASD. The first generation (F1) VPA-exposed offspring exhibited autistic-like impaired sociability and increased marble burying. They also showed increased seizure susceptibility, hyperactivity and decreased anxiety. We mated the VPA-exposed F1 male offspring with naïve females to produce the second generation (F2), and then similarly mated the F2 to deliver the third generation (F3). Remarkably, the autism-like behavioural phenotypes found in F1 persisted to the F2 and F3. Additionally, the frontal cortices of F1 and F3 showed some imbalanced expressions of excitatory/inhibitory synaptic markers, suggesting a transgenerational epigenetic inheritance. These results open the idea that E/I imbalance and ASD-like behavioural changes induced by environmental insults in mice can be epigenetically transmitted, at least, to the third generation. This study could help explain the unprecedented increase in ASD prevalence.