Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder / W. FYKE in Autism Research, 14-9 (September 2021)  

Public ISBD [article]  inAutism Research > 14-9 (September 2021) . - p.1854-1872 Titre : Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; Valerie LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur Article en page(s) : p.1854-1872 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder [Texte imprimé et/ou numérique] / W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; Valerie LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur . - p.1854-1872. Langues : Anglais (eng) in Autism Research > 14-9 (September 2021) . - p.1854-1872 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

Pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-?, induces autism spectrum disorder-like and co-morbid phenotypes in adult C57BL/J mice / W. FYKE in Autism Research, 14-7 (July 2021)  

Public ISBD [article]  inAutism Research > 14-7 (July 2021) . - p.1375-1389 Titre : Pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-?, induces autism spectrum disorder-like and co-morbid phenotypes in adult C57BL/J mice Type de document : Texte imprimé et/ou numérique Auteurs : W. FYKE, Auteur ; J. M. ALARCON, Auteur ; M. VELINOV, Auteur ; Kathryn K. CHADMAN, Auteur Article en page(s) : p.1375-1389 Langues : Anglais (eng) Mots-clés : Animals  Anxiety  Autism Spectrum Disorder  Disease Models, Animal  Endocannabinoids  Male  Mice  Mice, Inbred C57BL  Phenotype  Dgl-?  autism spectrum disorders  mouse models  neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Accumulating evidence links dysfunction in the endocannabinoid system (ECS) with the pathology of neurodevelopmental disorders, particularly autism spectrum disorder (ASD). Variants in ECS genes CNR1 and DAGLA are associated with neurological phenotypes in humans. The endocannabinoids (eCBs), 2-AG and AEA, which act at the primary cannabinoid receptor (CB1), mediate behaviors relevant to neurodevelopmental disorders. The overlap between these eCBs is poorly understood. Most ECS studies have focused on stress responses, anxiety, and epilepsy, however, its role in social behavior and communication has only recently come under investigation. This represents a critical gap in our understanding of the ECS and its relationship to ASD. Furthermore, the increasing prevalence of ASD and a lack of therapeutics emphasize a crucial need for novel therapeutic targets. To this aim, we used an inhibitor of the eCB producing enzyme DGL-?, DO34, and the CB1 inverse agonist, rimonabant, to evaluate the role of the primary eCB, 2-AG, in ASD. Adult male C57BL/6J mice were used in a series of behavioral paradigms which assessed social behavior, social communication, repetitive behaviors, anxiety and locomotor activity. DO34 and rimonabant increased anxiety-like behavior, while only DO34 induced hyperactivity, social deficits, and repetitive self-grooming behavior. These data indicate that reduced 2-AG bioavailability, or CB1 inhibition, each induce unique respective behavioral phenotypes relevant to neurodevelopmental disorders, particularly ASD. This suggests fundamental differences in CB1 signaling via 2-AG and the CB1 receptor itself, particularly for social behaviors, and that 2-AG signaling may represent a target for the development of novel therapeutics. LAY SUMMARY: Endocannabinoids play a critical role in the developing nervous system. Alterations in the endocannabinoid system are linked to neurodevelopmental disorders. Studies suggest these variants may play a critical role in the core symptoms of autism spectrum disorder. In this study, pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-?, induced a constellation of deficits in behavioral domains associated with autism. En ligne : http://dx.doi.org/10.1002/aur.2520 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] Pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-?, induces autism spectrum disorder-like and co-morbid phenotypes in adult C57BL/J mice [Texte imprimé et/ou numérique] / W. FYKE, Auteur ; J. M. ALARCON, Auteur ; M. VELINOV, Auteur ; Kathryn K. CHADMAN, Auteur . - p.1375-1389. Langues : Anglais (eng) in Autism Research > 14-7 (July 2021) . - p.1375-1389 Mots-clés : Animals  Anxiety  Autism Spectrum Disorder  Disease Models, Animal  Endocannabinoids  Male  Mice  Mice, Inbred C57BL  Phenotype  Dgl-?  autism spectrum disorders  mouse models  neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Accumulating evidence links dysfunction in the endocannabinoid system (ECS) with the pathology of neurodevelopmental disorders, particularly autism spectrum disorder (ASD). Variants in ECS genes CNR1 and DAGLA are associated with neurological phenotypes in humans. The endocannabinoids (eCBs), 2-AG and AEA, which act at the primary cannabinoid receptor (CB1), mediate behaviors relevant to neurodevelopmental disorders. The overlap between these eCBs is poorly understood. Most ECS studies have focused on stress responses, anxiety, and epilepsy, however, its role in social behavior and communication has only recently come under investigation. This represents a critical gap in our understanding of the ECS and its relationship to ASD. Furthermore, the increasing prevalence of ASD and a lack of therapeutics emphasize a crucial need for novel therapeutic targets. To this aim, we used an inhibitor of the eCB producing enzyme DGL-?, DO34, and the CB1 inverse agonist, rimonabant, to evaluate the role of the primary eCB, 2-AG, in ASD. Adult male C57BL/6J mice were used in a series of behavioral paradigms which assessed social behavior, social communication, repetitive behaviors, anxiety and locomotor activity. DO34 and rimonabant increased anxiety-like behavior, while only DO34 induced hyperactivity, social deficits, and repetitive self-grooming behavior. These data indicate that reduced 2-AG bioavailability, or CB1 inhibition, each induce unique respective behavioral phenotypes relevant to neurodevelopmental disorders, particularly ASD. This suggests fundamental differences in CB1 signaling via 2-AG and the CB1 receptor itself, particularly for social behaviors, and that 2-AG signaling may represent a target for the development of novel therapeutics. LAY SUMMARY: Endocannabinoids play a critical role in the developing nervous system. Alterations in the endocannabinoid system are linked to neurodevelopmental disorders. Studies suggest these variants may play a critical role in the core symptoms of autism spectrum disorder. In this study, pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-?, induced a constellation of deficits in behavioral domains associated with autism. En ligne : http://dx.doi.org/10.1002/aur.2520 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

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