Developing cost-effective and disease-relevant animal models is essential for advancing biomedical research into human disorders. Here we investigate the feasibility of a pig model for autism spectrum disorder (ASD) using embryonic exposure to valproic acid (VPA), an antiepileptic drug known to increase ASD risk. We established experimental paradigms to assess the behavioral characteristics of these pig models. Administration of VPA to Bama miniature pigs (Sus scrofa domestica) during critical embryonic stages resulted in abnormal gait, increased anxiety levels, reduced learning capabilities and altered social patterns, while largely preserving social preference of treated piglets. Notably, we detected significant neuroanatomical changes in cortical regions associated with ASD in the VPA-treated pigs, including cortical malformation, increased neuronal soma size, decreased dendritic complexity and reduced dendritic spine maturation. Transcriptome analysis of the prefrontal cortex of VPA-treated pigs further revealed substantial alterations in the expression of genes linked to ASD, especially genes of the dopamine signaling pathway, highlighting the model’s relevance and potential for shedding light on ASD’s underlying neuropathological and molecular mechanisms. These findings suggest that pig models could serve as a promising alternative to traditional rodent models and provide a more ethical substitute for the use of primates in translational research on neurodevelopmental disorders.

开发具有成本效益且与疾病相关的动物模型对于推进人类疾病的生物医学研究至关重要。在这里，我们研究了使用胚胎暴露于丙戊酸 （VPA） 治疗自闭症谱系障碍 （ASD） 的猪模型的可行性，丙戊酸 （VPA） 是一种已知会增加 ASD 风险的抗癫痫药物。我们建立了实验范式来评估这些猪模型的行为特征。在关键胚胎阶段对巴马微型猪 （Sus scrofa domestica） 施用 VPA 导致步态异常、焦虑水平增加、学习能力下降和社会模式改变，同时在很大程度上保留了治疗仔猪的社会偏好。值得注意的是，我们在 VPA 处理的猪中检测到与 ASD 相关的皮质区域的显着神经解剖学变化，包括皮质畸形、神经元胞体大小增加、树突复杂性降低和树突棘成熟度降低。VPA 处理猪前额叶皮层的转录组分析进一步揭示了与 ASD 相关的基因表达的重大变化，尤其是多巴胺信号通路的基因，突出了该模型的相关性和揭示 ASD 潜在神经病理学和分子机制的潜力。这些发现表明，猪模型可以作为传统啮齿动物模型的有前途的替代品，并为在神经发育障碍的转化研究中使用灵长类动物提供更合乎道德的替代品。