Choi Chang Soon, Hong Minha, Kim Ki Chan, Kim Ji-Woon, Yang Sung Min, Seung Hana, Ko Mee Jung, Choi Dong-Hee, You Jueng Soo, Shin Chan Young, Bahn Geon Ho
Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701.
Department of Psychiatry, School of Medicine, Dankook University Hospital, Cheonan 330-715 ; Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul 130-702, Republic of Korea.
Biomol Ther (Seoul). 2014 Sep;22(5):406-13. doi: 10.4062/biomolther.2014.027. Epub 2014 Sep 30.
A substantial proportion of patients with autism spectrum disorder (ASD) display hyperactivity as a comorbid symptom. Exposure to valproic acid (VPA) during pregnancy produces ASD-like core behavioral phenotypes as well as hyperactivity in offspring both in human and experimental animals, which makes it a plausible model to study ASD-related neurobiological processes. In this study, we examined the effects of two of currently available attention defecit hyperactivity disorder (ADHD) medications, methylphenidate (MPH) and atomoxetine (ATX) targeting dopamine and norepinephrine transporters (DAT and NET), respectively, on hyperactive behavior of prenatally VPA-exposed rat offspring. In the prefrontal cortex of VPA exposed rat offspring, both mRNA and protein expression of DAT was increased as compared with control. VPA function as a histone deacetylase inhibitor (HDACi) and chromatin immunoprecipitation experiments demonstrated that the acetylation of histone bound to DAT gene promoter was increased in VPA-exposed rat offspring suggesting epigenetic mechanism of DAT regulation. Similarly, the expression of NET was increased, possibly via increased histone acetylation in prefrontal cortex of VPA-exposed rat offspring. When we treated the VPA-exposed rat offspring with ATX, a NET selective inhibitor, hyperactivity was reversed to control level. In contrast, MPH that inhibits both DAT and NET, did not produce inhibitory effects against hyperactivity. The results suggest that NET abnormalities may underlie the hyperactive phenotype in VPA animal model of ASD. Profiling the pharmacological responsiveness as well as investigating underlying mechanism in multiple models of ASD and ADHD may provide more insights into the neurobiological correlates regulating the behavioral abnormalities.
相当一部分自闭症谱系障碍（ASD）患者表现出多动这一合并症状。孕期接触丙戊酸（VPA）会在人类和实验动物的后代中产生类似ASD的核心行为表型以及多动症状，这使其成为研究ASD相关神经生物学过程的一个合理模型。在本研究中，我们分别检测了目前可用的两种注意力缺陷多动障碍（ADHD）药物，即靶向多巴胺转运体（DAT）的哌甲酯（MPH）和靶向去甲肾上腺素转运体（NET）的托莫西汀（ATX），对产前暴露于VPA的大鼠后代多动行为的影响。与对照组相比，暴露于VPA的大鼠后代前额叶皮质中DAT的mRNA和蛋白表达均增加。VPA作为组蛋白去乙酰化酶抑制剂（HDACi）发挥作用，染色质免疫沉淀实验表明，暴露于VPA的大鼠后代中与DAT基因启动子结合的组蛋白乙酰化增加，提示DAT调控的表观遗传机制。同样，NET的表达增加，可能是由于暴露于VPA的大鼠后代前额叶皮质中组蛋白乙酰化增加所致。当我们用NET选择性抑制剂ATX治疗暴露于VPA的大鼠后代时，多动症状恢复到对照水平。相比之下，抑制DAT和NET的MPH对多动没有产生抑制作用。结果表明，NET异常可能是ASD的VPA动物模型中多动表型的基础。分析多种ASD和ADHD模型中的药理反应性以及研究潜在机制，可能会为调节行为异常的神经生物学相关性提供更多见解。
