Treating a novel plasticity defect rescues episodic memory in Fragile X model mice

Wang, W; Cox, Brittney M.; Jia, Yousheng; Le, Aliza A.; Cox, Conor D.; Jung, Kwang-Mook; Hou, Bowen; Piomelli, Daniele; Gall, Christine M.; Lynch, Gary

doi:10.1038/mp.2017.221

Cited by 39 publications

(55 citation statements)

References 73 publications

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“…Therefore, we evaluated e cacy of boosting 2-AG levels by hydrolysis inhibitor JZL184 toward repetitive and stereotypical behaviors, hyperactivity, de cits in social and cognitive functioning in VPA-induced rats. Results here presented showed either acute or chronic JZL184 administration was able to relieve ASD-like behaviors, which were in line with previous reports in Fmr1 knock-out mice and Shank3B −/− mice [15,45,46].…”

Section: Discussionsupporting

confidence: 93%

The Alternations of Endocannabinoid System and its Therapeutic Potential in Autism Spectrum Disorder

Liu

Xie

Wang

et al. 2020

Preprint

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Background: Autism spectrum disorder (ASD) is a group of developmental disabilities whose etiology remains elusive. The endocannabinoid (eCB) system modulated neurotransmission and neuronal plasticity. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of ASD. Herein we investigated if there was disruption of eCB system in ASD and if pharmacological modulators of eCB system might have a therapeutic potential. Methods: We examined three major components of eCB system, namely, endogenous cannabinoids, their receptors and associated enzymes, in ASD children as well as in VPA-induced ASD animal model. Meanwhile we specially increased 2-arachidonylglycerol (2-AG) by administering JZL184, a selective inhibitor of monoacylglycerol lipase, the hydrolytic enzyme for 2-AG, and to examine ASD-like behaviors in VPA-induced rats. Results: Autistic children and VPA-induced rats exhibited the reduced eCBs content, elevated degrading enzymes, and up-regulation of CBRs. We found that repetitive and stereotypical behaviors, hyperactivity, sociability, social preference, and cognitive functioning were improved after acute and chronic JZL184 treatment. The major efficacy of JZL184 was observed at the dose of 3mg/kg for both affecting eCB system and ASD-like behaviors. Conclusions: There were a lower eCB signaling in autistic children and ASD animal model, and boosting 2-AG could ameliorate ASD-like phenotypes in animals. Collectively, the results suggest a novel approach to ASD treatment.

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Section: Discussionsupporting

confidence: 93%

The Alternations of Endocannabinoid System and its Therapeutic Potential in Autism Spectrum Disorder

Liu

Xie

Wang

et al. 2020

Preprint

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“…A homosynaptic CB 1 R-dependent eCB-LTP was also characterized in hippocampal granular cells of the dentate gyrus resulting from postsynaptic 2-AG synthesis upon high-frequency stimulation of the lateral perforant path (LPP; Wang et al, 2016Wang et al, , 2018a; Figure 1B). When activated, CB 1 R, detected presynaptically at LPP terminals using STORM microscopy, engage the presynaptic FAK/ROCK signaling pathway favoring glutamate release.…”

Section: Homosynaptic Ecb-mediated Ltpmentioning

confidence: 96%

Lights on Endocannabinoid-Mediated Synaptic Potentiation

Piette

Cui

Gervasi

et al. 2020

Front. Mol. Neurosci.

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The endocannabinoid (eCB) system is a lipid-based neurotransmitter complex that plays crucial roles in the neural control of learning and memory. The current model of eCB-mediated retrograde signaling is that eCBs released from postsynaptic elements travel retrogradely to presynaptic axon terminals, where they activate cannabinoid type-1 receptors (CB 1 Rs) and ultimately decrease neurotransmitter release on a shortor long-term scale. An increasing body of evidence has enlarged this view and shows that eCBs, besides depressing synaptic transmission, are also able to increase neurotransmitter release at multiple synapses of the brain. This indicates that eCBs act as bidirectional regulators of synaptic transmission and plasticity. Recently, studies unveiled links between the expression of eCB-mediated long-term potentiation (eCB-LTP) and learning, and between its dysregulation and several pathologies. In this review article, we first distinguish the various forms of eCB-LTP based on their mechanisms, resulting from homosynaptically or heterosynaptically-mediated processes. Next, we consider the neuromodulation of eCB-LTP, its behavioral impact on learning and memory, and finally, eCB-LTP disruptions in various pathologies and its potential as a therapeutic target in disorders such as stress coping, addiction, Alzheimer's and Parkinson's disease, and pain. Cannabis is gaining popularity as a recreational substance as well as a medicine, and multiple eCB-based drugs are under development. In this context, it is critical to understand eCB-mediated signaling in its multi-faceted complexity. Indeed, the bidirectional nature of eCB-based neuromodulation may offer an important key to interpret the functions of the eCB system and how it is impacted by cannabis and other drugs.

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“…104 Reduced endocannabinoid activity was demonstrated in several animal models of ASD, 105 including monogenic (fragile-X, 106 neuroligin 3 107 ), polygenic (BTBR 105 ), and environmental (rat valproic acid 108 ) models. Activation of the endocannabinoid system [105][106][107][108] and administration of CBD 105 have been shown to restore social deficits in some models. A single oral administration of 600 mg CBD to 34 men (17 neurotypicals and 17 with ASD) increased prefrontal gamma-aminobutyric acid (GABA) activity in neurotypicals and decreased GABA activity in those with ASD.…”

Section: Medical Cannabis For Children With Autism Spectrum Disordermentioning

confidence: 99%

Medical Cannabis in Children

Aran¹,

Cayam-Rand²

2020

Rambam Maimonides Med J

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Treating a novel plasticity defect rescues episodic memory in Fragile X model mice

Cited by 39 publications

References 73 publications

The Alternations of Endocannabinoid System and its Therapeutic Potential in Autism Spectrum Disorder

The Alternations of Endocannabinoid System and its Therapeutic Potential in Autism Spectrum Disorder

Lights on Endocannabinoid-Mediated Synaptic Potentiation

Medical Cannabis in Children

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