Chu Ming-Chia, Wu Han-Fang, Lee Chi-Wei, Wu Chi-Chun, Chi Hsiang, Ko Chiung-Yuan, Lee Yi-Chao, Tang Chih-Wei, Chen Po See, Lin Hui-Ching
Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Department of Optometry, MacKay Medical College, New Taipei City, Taiwan.
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jan 10;136:111190. doi: 10.1016/j.pnpbp.2024.111190. Epub 2024 Nov 5.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social defects often accompanied with emotional comorbidities. Aberrations in synaptic function and plasticity are the core feature in the pathophysiology of ASD. Targeting soluble epoxide hydrolase (sEH) has been found to exert protection in a wide-range of pathological conditions. However, the regulation of sEH deficiency on the synaptic deficits of ASD and the underlying mechanisms remain unclear. The valproate (VPA)-treated ASD animal model with genetic sEH knockout was applied in the present study. The results showed that the sEH expression was significantly increased in the prefrontal cortex of VPA-treated animals. Although no effect was found on tail malformation and body weight loss, genetic sEH deletion alleviated social deficits, and fear learning and memory extinction in the VPA-treated mice. After a series of electrophysiological assessments, we found that the beneficial effects of sEH deletion focused on the long-term synaptic plasticity, rather than presynaptic efficiency, in the VPA-treated mice. Furthermore, we observed that the dysregulated AMPK-mTOR pathway was restored under genetic sEH deletion in VPA-treated mice. Taken together, these findings uncovered an important role of sEH deficiency in the synaptic dysfunctions of ASD mediated by AMPK-mTOR pathway, providing a novel therapeutic target for ASD.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社交缺陷，常伴有情绪共病。突触功能和可塑性异常是ASD病理生理学的核心特征。已发现靶向可溶性环氧化物水解酶（sEH）在多种病理状况下具有保护作用。然而，sEH缺乏对ASD突触缺陷的调节作用及其潜在机制仍不清楚。本研究应用了基因敲除sEH的丙戊酸（VPA）处理的ASD动物模型。结果显示，VPA处理动物的前额叶皮质中sEH表达显著增加。虽然未发现对尾巴畸形和体重减轻有影响，但基因敲除sEH可减轻VPA处理小鼠的社交缺陷以及恐惧学习和记忆消退。经过一系列电生理评估，我们发现敲除sEH的有益作用集中在VPA处理小鼠的长期突触可塑性上，而非突触前效率。此外，我们观察到在VPA处理的小鼠中，基因敲除sEH后失调的AMPK-mTOR通路得以恢复。综上所述，这些发现揭示了sEH缺乏在由AMPK-mTOR通路介导的ASD突触功能障碍中的重要作用，为ASD提供了一个新的治疗靶点。
