Targeting the inhibition of fatty acid amide hydrolase ameliorate the endocannabinoid-mediated synaptic dysfunction in a valproic acid-induced rat model of Autism

Han Fang Wu, Ting Yi Lu, Ming Chia Chu, Po See Chen, Chi Wei Lee, Hui Ching Lin

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number107736
JournalNeuropharmacology
Volume162
DOIs
Publication statusPublished - 2020 Jan 1

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Endocannabinoids
Valproic Acid
Autistic Disorder
Prefrontal Cortex
Acids
Metabotropic Glutamate Receptors
Social Behavior
Genetic Models
Interpersonal Relations
Emotions
Inhibition (Psychology)
Autism Spectrum Disorder
fatty-acid amide hydrolase
Depression
Phenotype
Brain
Enzymes
cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Targeting the inhibition of fatty acid amide hydrolase ameliorate the endocannabinoid-mediated synaptic dysfunction in a valproic acid-induced rat model of Autism",
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.",
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Targeting the inhibition of fatty acid amide hydrolase ameliorate the endocannabinoid-mediated synaptic dysfunction in a valproic acid-induced rat model of Autism. / Wu, Han Fang; Lu, Ting Yi; Chu, Ming Chia; Chen, Po See; Lee, Chi Wei; Lin, Hui Ching.

In: Neuropharmacology, Vol. 162, 107736, 01.01.2020.

Research output: Contribution to journalArticle

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