Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild to moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no available treatments to ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with sub-chronic (10 d) JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiac function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

• Publication year

  2021

• Venue

  bioRxiv

• Publication date

  2021-08-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/2021.08.16.456474PMID 36217821PMCID 9553213
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Clinical Data on Canabinoids: Translational Research in the Treatment of Autism Spectrum Disorders

  2022cited by this paper
• Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A 12‐Week, Randomized, Controlled Study

  2021cited by this paper
• Endocannabinoid Modulation Using Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A Phase 1 Randomized, Placebo-Controlled Study

  2021cited by this paper
• Williams syndrome

  2021cited by this paper
• EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

  2020cited by this paper
• Neurobiology of cannabinoid receptor signaling


  2020cited by this paper
• Health Care Supervision for Children With Williams Syndrome

  2020cited by this paper
• Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

  2020cited by this paper
• Protein Kinase C-Gamma Knockout Mice Show Impaired Hippocampal Short-Term Memory While Preserved Long-Term Memory

  2020cited by this paper
• Guidelines for Performing a Comprehensive Transthoracic Echocardiographic Examination in Adults: Recommendations from the American Society of Echocardiography.

  2019cited by this paper
• Use of the Vsoc-maze to Study Sociability and Preference for Social Novelty in Rodents.

  2019influential reference
• Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain

  2019cited by this paper
• Autophagy in the Heart.

  2019cited by this paper
• Williams syndrome: recent advances in our understanding of cognitive, social and psychological functioning

  2019cited by this paper
• Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome.

  2019cited by this paper
• An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability.

  2019cited by this paper
• Cardiovascular disease in Williams syndrome

  2018cited by this paper
• Endocannabinoid and Muscarinic Signaling Crosstalk in the 3xTg-AD Mouse Model of Alzheimer’s Disease

  2018cited by this paper
• Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model

  2018cited by this paper
• Endocannabinoid Signaling in the Control of Social Behavior.

  2017cited by this paper
• The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models

  2017cited by this paper
• Anxiety in Williams Syndrome: The Role of Social Behaviour, Executive Functions and Change Over Time

  2017cited by this paper
• Social defeat leads to changes in the endocannabinoid system: An overexpression of calreticulin and motor impairment in mice.

  2016cited by this paper
• Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play

  2016cited by this paper
• Neurobiology of social behavior abnormalities in autism and Williams syndrome

  2016cited by this paper
• The endocannabinoid system in guarding against fear, anxiety and stress

  2015cited by this paper
• Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences

  2015cited by this paper
• Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

  2014cited by this paper
• Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder.

  2014cited by this paper
• The Interplay Between Anxiety and Social Functioning in Williams Syndrome

  2014cited by this paper
• CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice.

  2013cited by this paper
• Targeting the endocannabinoid system in the treatment of fragile X syndrome

  2013cited by this paper
• Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome

  2013cited by this paper
• Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

  2013influential reference
• Sensitivity of the Autonomic Nervous System to Visual and Auditory Affect Across Social and Non-Social Domains in Williams Syndrome

  2012cited by this paper
• Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

  2012cited by this paper
• clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters

  2012cited by this paper
• Multiple functions of endocannabinoid signaling in the brain.

  2012cited by this paper
• 'Too withdrawn' or 'too friendly': considering social vulnerability in two neuro-developmental disorders.

  2012influential reference
• Research in Developmental Disabilities MRI amygdala volume in Williams Syndrome

  2011cited by this paper
• Effects of Endocannabinoid System Modulation on Cognitive and Emotional Behavior

  2011cited by this paper
• Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses.

  2011cited by this paper
• Abnormalities in neural processing of emotional stimuli in Williams syndrome vary according to social vs. non-social content

  2010cited by this paper
• Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system

  2010cited by this paper
• Mental health problems in adults with Williams syndrome.

  2010cited by this paper
• Animal models of Williams syndrome

  2010cited by this paper
• Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research

  2010cited by this paper
• Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling

  2009cited by this paper
• Roles of the endocannabinoid system in learning and memory.

  2009cited by this paper
• Looking at movies and cartoons: eye-tracking evidence from Williams syndrome and autism.

  2009cited by this paper
• Mechanisms and treatment of cardiovascular disease in Williams-Beuren syndrome.

  2008cited by this paper
• Perceiving facial and vocal expressions of emotion in individuals with Williams syndrome.

  2006cited by this paper
• Outcome in adult life for people with Williams syndrome-- results from a survey of 239 families.

  2006cited by this paper
• Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome.

  2005cited by this paper
• Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension

  2004cited by this paper
• Williams-Beuren Syndrome: A Model of Recurrent Genomic Mutation

  2003cited by this paper
• Cardiac hypertrophy: A matter of translation

  2003cited by this paper
• Functions of cannabinoid receptors in the hippocampus.

  2002cited by this paper
• Prevalence Estimation of Williams Syndrome

  2002cited by this paper
• The influence of antihypertensive drug treatment on the prevention and regression of left ventricular hypertrophy

  2000cited by this paper
• I. The Neurocognitive Profile of Williams Syndrome: A Complex Pattern of Strengths and Weaknesses

  2000cited by this paper
• Williams syndrome: cognition, personality, and adaptive behavior.

  2000cited by this paper
• The influence of antihypertensive drug treatment on the prevention and regression of left ventricular hypertrophy.

  2000cited by this paper
• The influence of antihypertensive drug treatment on the prevention and regression of left ventricular hypertrophy *

  1999cited by this paper
• Adults with Williams syndrome

  1998cited by this paper
• Social-emotional and behavioral adjustment in children with Williams-Beuren syndrome.

  1994cited by this paper
• Citation for Published Item: Use Policy Spontaneous and Cued Gaze-following in Autism and Williams Syndrome Spontaneous and Cued Gaze-following in Autism and Williams Syndrome

  year unknowncited by this paper

• 2-AG as a potential biomarker for predicting response to short-term fluoxetine treatment in a mouse model of depression

  2026cites this paper
• Metabolomic profiles in serum uncover novel biomarkers in children with Williams–Beuren syndrome

  2025influential citation
• Brain Monoamine Deficits in the CD Mouse Model of Williams–Beuren Syndrome

  2025cites this paper
• Sub‐chronic administration of AM6545 enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice

  2025cites this paper
• How copy number variations shape brain developmental disorders: Unraveling the synaptic puzzle.

  2025cites this paper
• Synthesis and Pharmacological Characterization of a Novel Cannabinoid Receptor 1 Antagonist

  2025cites this paper
• Boosting 2-arachidonoylglycerol, but not N-acylethanolamine, ameliorates autism symptoms in VPA-exposed rats by modulating abnormal neuroinflammation.

  2025cites this paper
• Integrating machine learning and WGCNA for nomogram diagnostic model unveiling previously unrecognized phase separation-related molecular markers and immuno-cytotoxic pathways in Williams-Beuren syndrome

  2025cites this paper
• Generation of two induced pluripotent stem cell lines from patients with Williams syndrome

  2024cites this paper
• Sub-chronic peripheral CB1R inhibition enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice

  2024cites this paper
• Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer’s Disease

  2024cites this paper
• Synthesis and pharmacological characterization of UVI3502, a novel cannabinoid receptor 1 (CB1) antagonist/inverse agonist

  2024cites this paper
• Endocannabinoid System: Chemical Characteristics and Biological Activity

  2023cites this paper
• GABAB1 Receptor Knockdown in Prefrontal Cortex Induces Behavioral Aberrations Associated with Autism Spectrum Disorder in Mice.

  2023cites this paper
• Early Administration of the Phytocannabinoid Cannabidivarin Prevents the Neurobehavioral Abnormalities Associated with the Fmr1-KO Mouse Model of Fragile X Syndrome

  2023cites this paper
• Mechanisms of copy number variants in neuropsychiatric disorders: From genes to therapeutics.

  2023cites this paper
• Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis

  2023cites this paper
• Dysfunctional Mitochondria in the Cardiac Fibers of a Williams–Beuren Syndrome Mouse Model

  2023cites this paper
• Early Neurobehavioral Characterization of the CD Mouse Model of Williams–Beuren Syndrome

  2023influential citation