Abstract
Autism spectrum disorder (ASD) is a group of developmental disabilities, the aetiology of which remains elusive. The endocannabinoid (eCB) system modulates neurotransmission and neuronal plasticity. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of ASD. We investigated whether there is a disruption to the eCB system in ASD and whether pharmacological modulation of the eCB system might offer therapeutic potential. We examined three major components of the eCB system-endogenous cannabinoids, their receptors and associated enzymes-in ASD children as well as in the valproic acid (VPA) induced animal model in autism. Furthermore, we specifically increased 2-arachidonoylglycerol (2-AG) levels by administering JZL184, a selective inhibitor of monoacylglycerol lipase which is the hydrolytic enzyme for 2-AG, to examine ASD-like behaviours in VPA-induced rats. Results showed that autistic children and VPA-induced rats exhibited reduced eCB content, increased degradation of enzymes and upregulation of CBRs. We found that repetitive and stereotypical behaviours, hyperactivity, sociability, social preference and cognitive functioning improved after acute and chronic JZL184 treatment. The major efficacy of JZL184 was observed after administration of a dosage regimen of 3 mg kg-1, which affected both the eCB system and ASD-like behaviours. In conclusion, a reduced eCB signalling was observed in autistic children and in the ASD animal model, and boosting 2-AG could ameliorate ASD-like phenotypes in animals. Collectively, the results suggested a novel approach to ASD treatment.
Highlights
Autism spectrum disorder (ASD) is a collection of heterogeneous neurodevelopmental disorders and it is defined by impairment in communication and social interactions, as well as restricted, repetitive patterns of behaviour [1]
We examined all three major components of the endogenous cannabinoids (eCBs) system, namely, eCBs (AEA, PEA, OEA and 2-AG), CBRs (CB1R and type 2 cannabinoid receptors (CB2R)) and related catalyzed enzymes (NAPE-PLD, fatty acid amide hydrolase (FAAH), diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL)), in ASD children as well as in the valproic acid (VPA)-induced ASD animal model, in order to comprehensively characterize the involvement of the eCB system in the pathogenesis of ASD
This study aimed to highlight that ASD children and ASD model rats have been found to exhibit disruption of the eCB system, and that pharmacological modulators of the eCB system may offer therapeutic potential in ASD
Summary
Autism spectrum disorder (ASD) is a collection of heterogeneous neurodevelopmental disorders and it is defined by impairment in communication and social interactions, as well as restricted, repetitive patterns of behaviour [1]. The most recent prevalence estimate of ASD reached 1.85% (one in 54) among children aged 8 years old [3]. A multitude of recent publications have suggested that ASD is related to abnormalities in synaptic function. The endocannabinoid (eCB) system has attracted increasing interest for its potential in the onset and/or progression of ASD, as this system could modulate different neurotransmitter system, synaptic excitation and inhibition (E/I balance) and plasticity in the brain, and it could be associated with social interaction, motor control, repetitive behaviours, emotional processing, learning and memory
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