The Endocannabinoid System and Autism Spectrum Disorders: and the associated metabolic enzymes, constitute the endocannabinoid (EC). The Endocannabinoids System (ES) consists of a family of locally produced factors and their respective receptors connect these two systems. The Endocannabinoid System and Autism Spectrum Disorders: Insights movements, frequently associated with general cognitive deficits.
and How Are System Autism Connected? Endocannabinoid the
These behavioral phenotypes in the offspring were correlated with synaptic abnormalities, including increased cell density and excitability of pyramidal neurons, enhanced postsynaptic glutamatergic responses to NMDA-induced synaptic plasticity, as well as altered glia reactivity [ 84 ]. Although post-natal LPS administration is not recognized as a model of ASD, data collected further suggest that FAAH inhibition may represent a potential approach for the treatment of disorders involving impaired sociability.
Early-life inflammation induced by a single LPS injection at postnatal day PND 14 decreased adolescent social play and non-play behavior both in male and in female rats. A similar improvement was observed after direct PF injection into the basolateral amygdala, suggesting that altered AEA signaling in this brain region plays a central role in mediating LPS-induced social impairments at least in females.
Many morphological and neurochemical abnormalities have been reported in ASD patients as well as in animal models, reflecting the heterogeneous and complex nature of this group of disorders. Such diversity poses a great challenge and hampers the identification of possible common pathophysiological mechanisms in ASD.
However, very little information has been thus far available regarding the possible mechanisms through which the EC system could affect ASD-like behaviors.
For instance, the reported prosocial effects of AEA in animal models of ASD might arise from an interaction with oxytocin, a neuropeptide that promotes parental and social bonding. Indeed, recent evidence has highlighted that oxytocin stimulates AEA release in the nucleus accumbens, a key region for the reinforcing properties of both natural rewards and drugs of abuse, and, importantly, AEA-mediated signaling is required for the prosocial effects of this neuropeptide [ 91 ].
This suggests that oxytocin-driven AEA signaling may be defective in ASD; hence, a correction of such deficits supposedly offers a novel strategy to treat the social impairments associated with ASD. Additionally, it has been shown that the amelioration of cognitive deficits after chronic rimonabant administration in Fmr1 knockout mice was associated with the normalization of the hippocampal mTOR signaling pathway [ 42 ], suggesting that the procognitive effects elicited by CB1 receptor blockade may be partly dependent upon restoration of this signaling pathway in the hippocampus.
This is consistent with the observation that mTOR signaling is crucially involved in memory consolidation [ 92 ], and its genetic modulation prevents some of the pathological features in Fmr1 knockout mice [ 93 ]. There is also evidence that ECs might modulate ASD symptoms via interaction with immune system cells. Indeed, changes in AEA metabolism and CB2 receptors were observed in peripheral blood mononuclear cells [ 95 ] and blood monocyte-derived macrophage cells [ 96 ] from autistic patients, suggesting that the EC system could play a role in the immunological dysfunctions associated with ASD.
As retrograde EC signaling at CB1 receptors is a key regulator of synaptic plasticity both at inhibitory and excitatory synapses in the adult brain [ 99 ], dysfunctions of the EC system could sustain ASD phenotypes as a consequence of unbalanced excitatory and inhibitory neurotransmission. Understanding the time course of the alterations of the EC system in animal models of ASD could help to dissect the contribution of this system in the pathogenesis of these neurodevelopmental conditions.
Although the preclinical findings seem to suggest that pharmacological interventions aimed at modulating the EC system could be beneficial for relieving symptoms associated with ASD Table 2 , their preliminary nature does not allow any definite conclusion to be drawn concerning potential therapeutic exploitations. Effects of pharmacological manipulations of the endocannabinoid EC system in animal models of autism spectrum disorder ASD.
Converging data indicate that enhancing AEA signaling through inhibition of its degradation exerts prosocial effects in different animal models of ASD. In addition, CB1 receptor blockade, either acute or chronic, seems to have beneficial effects towards cognitive deficits, at least in mouse models of FXS.
Remarkably, in most of the studies, the drugs were administered systemically. However, the alterations of the EC system reported in animal models of ASD Table 3 appear to be different depending on the brain region considered, possibly suggesting a different contribution to ASD-like symptoms.
If so, any potential therapeutic approach is unlikely to involve a single targeted molecule. National Center for Biotechnology Information , U.
Int J Mol Sci. Published online Sep 7. Find articles by Marina Gabaglio. Author information Article notes Copyright and License information Disclaimer. Received Jul 24; Accepted Sep 4. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution CC BY license http: This article has been cited by other articles in PMC.
Abstract Autism spectrum disorder ASD defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Introduction Endocannabinoids ECs are arachidonic acid-derived compounds that, together with their receptors and the associated metabolic enzymes, constitute the endocannabinoid EC system, a neuromodulatory network of lipid signaling pathways [ 1 ].
Table 1 Pharmacological modulators of the endocannabinoid EC system tested in animal models of autism spectrum disorder ASD. Open in a separate window. EC-modulation of ASD-Like Behaviors According to the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders DSM-5 , ASD comprises a heterogeneous group of neurological conditions characterized by impaired social communication functions and the presence of restricted, repetitive patterns of behavior or interests that start to emerge in the early developmental period.
Neuroligin-3 NLGN3 Mouse Models NLGNs are postsynaptic cell adhesion molecules required for synaptic function; they orchestrate the maturation and function of both excitatory and inhibitory synapses in the mammalian brain [ 46 , 47 ]. BTBR Mouse Model In addition to the genetically modified rodent models of ASD, several inbred mouse strains incorporate face validity as ASD models, because they display robust and well-replicated social deficits and repetitive behaviors.
The EC System in Environmental-Based Models Although the most commonly suggested etiology of ASD is through the hereditary genetic characteristics identified as high risk genes for ASD, exposure to environmental factors in the prenatal and early postnatal periods imposes a significant contribution to ASD development [ 60 , 61 ].
Prenatal VPA Exposure Among environmental animal models that show both construct and face validity to ASD, the VPA rat model represents an excellent system to test and develop novel behavioral and drug therapies. Postnatal LPS Injection Both viral and bacterial infections during pregnancy have been linked to an increased risk to develop ASD in the offspring [ 76 ].
Possible Mechanisms Many morphological and neurochemical abnormalities have been reported in ASD patients as well as in animal models, reflecting the heterogeneous and complex nature of this group of disorders. Conclusions Although the preclinical findings seem to suggest that pharmacological interventions aimed at modulating the EC system could be beneficial for relieving symptoms associated with ASD Table 2 , their preliminary nature does not allow any definite conclusion to be drawn concerning potential therapeutic exploitations.
Table 2 Effects of pharmacological manipulations of the endocannabinoid EC system in animal models of autism spectrum disorder ASD. Conflicts of Interest The authors declare no conflict of interest. The endocannabinoid system and its modulation by phytocannabinoids. Endocannabinoids as regulators of transient receptor potential TRP channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs.
From surface to nuclear receptors: The endocannabinoid family extends its assets. Endocannabinoids and endocannabinoid-related mediators: Targets, metabolism and role in neurological disorders. Modulating the endocannabinoid system in human health and disease—successes and failures. Endocannabinoids and mental disorders. Neuromodulatory functions of the endocannabinoid system.
The endocannabinoid system in the regulation of emotions throughout lifespan: A discussion on therapeutic perspectives. Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats. Divergent effects of anandamide transporter inhibitors with different target selectivity on social play behavior in adolescent rats.
Bidirectional cannabinoid modulation of social behavior in adolescent rats. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex.
Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Regulation of the hypothalamic-pituitary-adrenal axis circadian rhythm by endocannabinoids is sexually diergic.
Has it got rhythm? Variations in the human cannabinoid receptor CNR1 gene modulate striatal responses to happy faces. Variation in the human cannabinoid receptor CNR1 gene modulates gaze duration for happy faces.
Cannabinoid receptor 1 CNR1 gene: Impact on antidepressant treatment response and emotion processing in major depression. Research into causes and intervention.
Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Translating human deficits into mouse behavior. Translational animal models of autism and neurodevelopmental disorders. Genetic and non-genetic animal models for autism spectrum disorders ASD Reprod.
Clinical and neurobiological relevance of current animal models of autism spectrum disorders. Modeling autism-relevant behavioral phenotypes in rats and mice: Fragile X and autism: Intertwined at the molecular level leading to targeted treatments. Modeling fragile X syndrome in the Fmr1 knockout mouse. Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits. Dendritic spine structural anomalies in fragile-X mental retardation syndrome.
Altered synaptic plasticity in a mouse model of fragile X mental retardation. Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome.
Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Possible therapeutic doses of cannabinoid type 1 receptor antagonist reverses key alterations in fragile X syndrome mouse model. Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome. Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment.
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Neuroligins and neurexins link synaptic function to cognitive disease.
Paris autism research international sibpair, S. The ArgCys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. Autism-linked neuroligin-3 RC mutation differentially alters hippocampal and cortical synaptic function.
Model of a monogenic heritable form of autism with an olfactory deficit. Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Increased cortical inhibition in autism-linked neuroligin-3RC mice is due in part to loss of endocannabinoid signaling.
Consequences of cannabinoid and monoaminergic system disruption in a mouse model of autism spectrum disorders. The BTBR mouse model of autism spectrum disorders has learning and attentional impairments and alterations in acetylcholine and kynurenic acid in prefrontal cortex.
An unusual behavioral phenotype. Genetic heritability and shared environmental factors among twin pairs with autism. The familial risk of autism.
Exploring the validity of valproic acid animal model of autism. In utero exposure to valproic acid and autism—a current review of clinical and animal studies. Fetal valproate syndrome and autism: Additional evidence of an association. Valproic acid in pregnancy: How much are we endangering the embryo and fetus?
A clinical study of 57 children with fetal anticonvulsant syndromes. Behavioral alterations in rats prenatally exposed to valproic acid: Animal model of autism. Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Sex and gender differences in autism spectrum disorder: Summarizing evidence gaps and identifying emerging areas of priority.
Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Another discovered this same prevalence in the upregulation of CB 2 , but in human subjects 6. In one study, an autistic child that was given THC for six months reported significant improvements in hyperactivity, lethargy, irritability, stereotypy and inappropriate speech 4.
In addition, mice with similar behavioral characteristics to autistic humans saw a reduction in depression and were able to remain focused on running on the spinning wheel apparatus after given cannabinoids 5.
Another study found that boosting cannabinoids in the brain helps to correct behavioral issues that are related to fragile x syndrome, the most common known genetic cause of autism 3. Pennsylvania and Minnesota effective as of July are the only states to have approved medical cannabis for autism.
A number of other states do, however, consider allowing cannabis for conditions that are not specified in their list of approved conditions. An approval or physician recommendation is required for consideration. An autistic child given THC for six months reported significant reductions in the symptoms of autism.
Use of dronabinol deltaTHC in autism: A prospective single-case-study with an early infantile autistic child. Mice with similar behavioral characteristics to autistic humans saw an enhanced reduction in depression and were able to remain focused on running on the spinning wheel apparatus.
Consequences of cannabinoid and monoaminergic system disruption in a mouse model of autism spectrum disorders. Your email address will not be published. Federal Tax ID The information contained in this website is for general information and educational purposes only. It does not constitute medical advice. Therefore, any reliance you place on such information is strictly at your own risk. Please check with your medical doctor before starting or changing your CBD routine. I accept the terms and conditions and am aware that this notification will not appear again during an unspecified time.
Overview of Autism Autism spectrum disorder ASD is a term used to classify a range of complex neurodevelopment disorders that are characterized, in varying degrees, by social interaction difficulties, verbal and physical communication problems, and restricted and repetitive patterns of behavior. Effects of Cannabinoids and CBD on Autism Researchers have found what they believe to be a potential link between autism and the cannabinoid 2 receptors CB 2 within the endocannabinoid system.
States That Have Approved Medical Cannabis for Autism Pennsylvania and Minnesota effective as of July are the only states to have approved medical cannabis for autism. National Institute of Neurological Disorders and Stroke.
Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron , 78 3 ,
So far, studies have linked the endocannabinoid system to the the endocannabinoid system and the symptoms of autism are indirect, the. Alger added that, if the endocannabinoid system does turn out to be connected to autism in humans, medical marijuana could turn out to hold. The Endocannabinoid System and autism spectrum disorders: how cannabis Neuroligins are part of a family of neuronal cell surface proteins that “connect.