Sakade Yuki, Yamanaka Kumiko, Soumiya Hitomi, Furukawa Shoei, Fukumitsu Hidefumi
Laboratory of Molecular Biology, Department of Biofunctional Analysis, Gifu Pharmaceutical University.
Biomed Res. 2019;40(5):179-188. doi: 10.2220/biomedres.40.179.
Single prenatal exposure to valproic acid (VPA) in rodents is a widely used preclinical model of autism spectrum disorder (ASD). Continuous prenatal VPA exposure has been recently proposed as a new ASD model that closely captures the neuropathological features of ASD, including increases in cerebral cortex volume and the number of cortical upper layer neurons. We investigated the influence of prenatal VPA exposure on the behavior of adult offspring of pregnant dams that received intraperitoneal injections of VPA twice on one day during the genesis of cortical upper layer neurons. Mice exposed to VPA at E14 (E14-VPA) showed typical behavior abnormalities including reduced social interaction, hyperactivity, and poor maze learning due to attention deficit/impulsivity relative to healthy controls. Histological analysis revealed that E14-VPA mice had significantly increased neuronal density and impaired neural activity in the prefrontal cortex, but not the somatosensory area, which is likely linked to the observed abnormalities in social behavior. These results suggest that this VPA exposure method is a good model for gaining new insights into the underlying neuropathology of ASD.
啮齿动物单次产前暴露于丙戊酸（VPA）是一种广泛应用的自闭症谱系障碍（ASD）临床前模型。最近，持续产前暴露于VPA被提出作为一种新的ASD模型，该模型能密切捕捉ASD的神经病理学特征，包括大脑皮层体积增加和皮质上层神经元数量增加。我们研究了产前暴露于VPA对怀孕母鼠成年后代行为的影响，这些母鼠在皮质上层神经元形成期间于一天内接受了两次腹腔注射VPA。在胚胎第14天（E14）暴露于VPA的小鼠（E14-VPA）表现出典型的行为异常，包括社交互动减少、多动以及由于注意力缺陷/冲动导致的迷宫学习能力差，相对于健康对照组而言。组织学分析显示，E14-VPA小鼠前额叶皮质的神经元密度显著增加且神经活动受损，但躯体感觉区未受影响，这可能与观察到的社交行为异常有关。这些结果表明，这种VPA暴露方法是深入了解ASD潜在神经病理学的良好模型。
