Targeting the inhibition of fatty acid amide hydrolase ameliorate the endocannabinoid-mediated synaptic dysfunction in a valproic acid-induced rat model of Autism. (1st January 2020)

• Record Type: Journal Article
• Authors: Wu, Han-Fang; Lu, Ting-Yi; Chu, Ming-Chia; Chen, Po See; Lee, Chi-Wei; Lin, Hui-Ching
• Is Part Of: Neuropharmacology. Volume 162(2020)
• Publication Date: 2020-01-01
• Subjects: Autism spectrum disorder -- Prefrontal cortex -- Endocannabinoid system -- Long-term depression -- α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107736
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Highlights: URB597 improved socio-emotional behaviors and endocannabinoid-mediated synaptic plasticity in VPA-induced ASD offspring. The impaired eCB-LTD and mGluR-LTD was attributed to the dysfunctional of AMPAR trafficking in VPA-induced offspring. URB597 alleviated autistic behaviors and synaptopathology was mediated by facilitating the removal AMPAR subunits GluA1/2.