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      Plasma anandamide concentrations are lower in children with autism spectrum disorder

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          Abstract

          Background

          Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD ( N = 112).

          Findings

          Anandamide concentrations significantly differentiated ASD cases ( N = 59) from controls ( N = 53), such that children with lower anandamide concentrations were more likely to have ASD ( p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children ( p = 0.034).

          Conclusions

          These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

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          Most cited references10

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          Elevated Brain Cannabinoid CB1 Receptor Availability in Posttraumatic Stress Disorder: A Positron Emission Tomography Study

          Endocannabinoids and their attending cannabinoid type 1 receptor (CB1) have been implicated in animal models of posttraumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [11C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma controls [TC]) and those without such histories (healthy controls [HC]). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance (MR) imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [11C]OMAR, which measures volume of distribution (V T) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [11C]OMAR V T values (F(2,53)=7.96, p=.001; 19.5% and 14.5% higher, respectively) which were most pronounced in women (F(1,53)=5.52, p=.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively—OMAR V T, anandamide, and cortisol—correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.
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            Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.

            Neuroligins are postsynaptic cell-adhesion molecules that interact with presynaptic neurexins. Rare mutations in neuroligins and neurexins predispose to autism, including a neuroligin-3 amino acid substitution (R451C) and a neuroligin-3 deletion. Previous analyses showed that neuroligin-3 R451C-knockin mice exhibit robust synaptic phenotypes but failed to uncover major changes in neuroligin-3 knockout mice, questioning the notion that a common synaptic mechanism mediates autism pathogenesis in patients with these mutations. Here, we used paired recordings in mice carrying these mutations to measure synaptic transmission at GABAergic synapses formed by hippocampal parvalbumin- and cholecystokinin-expressing basket cells onto pyramidal neurons. We demonstrate that in addition to unique gain-of-function effects produced by the neuroligin-3 R451C-knockin but not the neuroligin-3 knockout mutation, both mutations dramatically impaired tonic but not phasic endocannabinoid signaling. Our data thus suggest that neuroligin-3 is specifically required for tonic endocannabinoid signaling, raising the possibility that alterations in endocannabinoid signaling may contribute to autism pathophysiology. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Alterations in the endocannabinoid system in the rat valproic acid model of autism.

              The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders. Copyright © 2013 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                dkarhson@stanford.edu
                krasin@stanford.edu
                jahloyda@stanford.edu
                rlibove@stanford.edu
                jenphil@stanford.edu
                allis@stanford.edu
                jgarner@stanford.edu
                ayhardan@stanford.edu
                kjparker@stanford.edu
                Journal
                Mol Autism
                Mol Autism
                Molecular Autism
                BioMed Central (London )
                2040-2392
                12 March 2018
                12 March 2018
                2018
                : 9
                : 18
                Affiliations
                [1 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Psychiatry and Behavioral Sciences, , Stanford University, ; 401 Quarry Rd., Stanford, CA 94305 USA
                [2 ]ISNI 0000000419368956, GRID grid.168010.e, Vincent Coates Foundation Mass Spectrometry Laboratory, , Stanford University, ; 333 Campus Dr., Stanford, CA 94305 USA
                [3 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Comparative Medicine, , Stanford University, ; 287 Campus Dr., Stanford, CA 94305 USA
                Article
                203
                10.1186/s13229-018-0203-y
                5848550
                29564080
                b4fe755e-60f0-4844-a54b-bb7206422ab7
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 13 November 2017
                : 5 March 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000893, Simons Foundation;
                Award ID: 93231
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: T32 MH019908
                Award Recipient :
                Funded by: Stanford University Mass Spectrometry
                Award ID: Vincent Coates Foundation Mass Spectrometry Seed Grant
                Award Recipient :
                Funded by: Teresa and Charles Michael Endowed Fund for Autism Research and Education
                Award ID: Gift Award
                Award Recipient :
                Funded by: Mosbacher Family Fund for Autism Research
                Award ID: Gift Award
                Award Recipient :
                Categories
                Short Report
                Custom metadata
                © The Author(s) 2018

                Neurosciences
                anandamide,autism spectrum disorder,blood biomarker,cannabinoid
                Neurosciences
                anandamide, autism spectrum disorder, blood biomarker, cannabinoid

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