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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
- Source :
- Neuropharmacology. 162
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
Autism Spectrum Disorder
Polyunsaturated Alkamides
Prefrontal Cortex
AMPA receptor
Arachidonic Acids
Receptors, Metabotropic Glutamate
Amidohydrolases
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Fatty acid amide hydrolase
Pregnancy
mental disorders
Genetic model
Animals
Receptors, AMPA
Enzyme Inhibitors
Long-term depression
Social Behavior
Pharmacology
Neuronal Plasticity
Long-Term Synaptic Depression
Valproic Acid
Anandamide
URB597
Endocannabinoid system
Rats
Disease Models, Animal
Protein Transport
030104 developmental biology
nervous system
chemistry
Metabotropic glutamate receptor
Prenatal Exposure Delayed Effects
Benzamides
lipids (amino acids, peptides, and proteins)
Female
Carbamates
Neuroscience
030217 neurology & neurosurgery
Endocannabinoids
Subjects
Details
- ISSN :
- 18737064
- Volume :
- 162
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....bb5d14294d8dfdff3aca71bcfcbf1902