Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan; Department of Optometry, Hsin-Sheng College of Medical Care and Management, Taoyuan, 32544, Taiwan.
Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
Neuropharmacology. 2020 Jan 1;162:107736. doi: 10.1016/j.neuropharm.2019.107736. Epub 2019 Aug 6.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social interaction impairment, stereotypical/repetitive behaviors and emotional deregulation. The endocannabinoid (eCB) system plays a crucial role in modulating the behavioral traits that are typically core symptoms of ASD. The major molecular mechanisms underlying eCB-dependent long-term depression (eCB-LTD) are mediated by group 1 metabotropic glutamate receptor (mGluR)-induced removal of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Recently, modulation of anandamide (AEA), one of the main endocannabinoids in the brain, has been reported to alter social behaviors in genetic models of ASD. On this basis, we investigated the effects of treatment and the synaptic mechanism underlying AEA-mediated signaling in prenatal exposure to valproic acid (VPA) in rats. We found that the social deficits, repetitive behaviors and abnormal emotion-related behaviors in VPA-exposed offspring were improved after treatment with an inhibitor of AEA degrading enzyme, URB597. Using an integrative approach combing electrophysiological and cellular mechanisms, the results showed that the impaired eCB-LTD, abnormal mGluR-mediated LTD (mGluR-LTD) and decreased removal of AMPAR subunits GluA1 and GluA2 were reversed by URB597 in the prefrontal cortex (PFC) of VPA-exposed offspring. Taken together, these results provide the first evidence that rescue of the ASD-like phenotype by URB597 is mediated by enhancing the mechanism of removal of AMPAR subunits GluA1/2 underlying AEA signaling in the PFC in a VPA-induced model of ASD.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征为社交互动受损、刻板/重复行为和情绪失调。内源性大麻素（eCB）系统在调节行为特征方面起着至关重要的作用，这些行为特征通常是 ASD 的核心症状。eCB 依赖性长时程抑制（eCB-LTD）的主要分子机制是通过 1 型代谢型谷氨酸受体（mGluR）诱导去除突触后α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）介导的。最近，据报道，内源性大麻素之一的花生四烯酸（AEA）的调节可改变 ASD 遗传模型中的社交行为。在此基础上，我们研究了在产前暴露于丙戊酸（VPA）的大鼠中，AEA 介导的信号转导的治疗效果及其突触机制。我们发现，经 URB597 治疗后，VPA 暴露后代的社交缺陷、重复行为和异常情绪相关行为得到改善。通过整合电生理和细胞机制的方法，结果表明，在 VPA 暴露后代的前额叶皮层（PFC）中，受损的 eCB-LTD、异常的 mGluR 介导的 LTD（mGluR-LTD）和 AMPAR 亚基 GluA1 和 GluA2 的去除减少被 URB597 逆转。总之，这些结果提供了第一个证据，即 URB597 通过增强 PFC 中 AEA 信号转导的 AMPAR 亚基 GluA1/2 去除机制，来挽救 VPA 诱导的 ASD 模型中的 ASD 样表型。
