The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy.
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.
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Chang Soon
CS
Choi
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Edson Luck
EL
Gonzales
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Ki Chan
KC
Kim
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Sung Min
SM
Yang
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Ji-Woon
JW
Kim
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Darine Froy
DF
Mabunga
Department of Pharmacy, Sahmyook University, Seoul, Korea.
Jae Hoon
JH
Cheong
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Seol-Heui
SH
Han
Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul, Korea.
Geon Ho
GH
Bahn
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul 143-701, Korea.
Chan Young
CY
Shin
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D014635:Valproic Acid / Q000009:adverse effects* / Q000494:pharmacology
D014635:Valproic Acid