Exposure to valproic acid during pregnancy induces autism endophenotypes in the male offspring

[Speaker] Mami Hirakawa:1
[Co-author] Akihiro Mouri:1,4, Kazuo Kunisawa:2, Yuko Mori:3, Moe Niijima:1, Hisayoshi Kubota:1, Tomoaki Teshigawara:3, Hidetsugu Fujigaki:3, Toshitaka Nabeshima:2,4, Kuniaki Saito:3,4
1:Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences, Japan, 2:Advanced Diagnostic System Research Laboratory, Fujita Health Universuty Graduate School of Health Science, Japan, 3:Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Science, Japan, 4:Japanese Drug Organization of Appropriate Use and Research, Japan

Background:Autism is the developmental disorders characterized by social disability and stereotypy. Although the pathogenesis of autism is still unknown, it is epidemiologically reported that administration of valproic acid (VPA) during pregnancy increases the risk of autism in the offspring. VPA activates the GABAergic neuronal system by inhibition of GABA transaminase. In this study, we investigated 1) whether autism-like behaviors are observed in the offspring exposed to VPA during pregnancy and 2) whether such behaviors are mediated via a functional change in GABAergic neuronal system.
Methoods:Pregnant C57Bl/6J mice were injected with VPA (500 mg/kg, i.p.) on gestational day 12. The offspring were measured spontaneous activity and grooming under a novel environment, subjected social interaction test and novel object recognition test. Protein levels of GABA neuronal system and intracellular signaling were measured by Western blottting.
Result:The male offspring exposed to VPA during pregnancy showed decrease in spontaneous activity, social interaction time, approach time for novel object, but increase in grooming time. Although such behavioral changes were not observed in female offspring.
Conclusion:Behavioral changes in male offspring exposed to VPA during pregnancy were associated with the autism-like symptom (decrease in spontaneous activity:loss of interest, increase in grooming time: stereotypy, decrease in social interaction time: social disability, decrease in approach time for novel object: congnitive dysfunction). Autism is more commonly diagnosed in males. Taken together three results, male offspring exposed to VPA during pregnancy showed autism endophenotypes. Now, we are investigating the functional linkage between GABAergic signaling and autism-like behaviors.
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