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Auteur N. A. COPPING |
Documents disponibles écrits par cet auteur (2)
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Developmental social communication deficits in the Shank3 rat model of phelan-mcdermid syndrome and autism spectrum disorder / Elizabeth L. BERG in Autism Research, 11-4 (April 2018)
[article]
Titre : Developmental social communication deficits in the Shank3 rat model of phelan-mcdermid syndrome and autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Elizabeth L. BERG, Auteur ; N. A. COPPING, Auteur ; J. K. RIVERA, Auteur ; M. C. PRIDE, Auteur ; Milo CAREAGA, Auteur ; M. D. BAUMAN, Auteur ; Robert F. BERMAN, Auteur ; P. J. LEIN, Auteur ; Hala HARONY-NICOLAS, Auteur ; Joseph D. BUXBAUM, Auteur ; J. ELLEGOOD, Auteur ; J. P. LERCH, Auteur ; M. WOHR, Auteur ; J. L. SILVERMAN, Auteur Article en page(s) : p.587-601 Langues : Anglais (eng) Mots-clés : Phelan McDermid Syndrome animal model autism behavior neurodevelopment shank social synapse Index. décimale : PER Périodiques Résumé : Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions. We report, for the first time, a call and response acoustic playback assay of bidirectional social communication in juvenile Shank3 rats. Interestingly, we found that Shank3-deficient null males did not demonstrate the enhanced social approach behavior typically exhibited following playback of pro-social USV. Concomitantly, we discovered that emission of USV in response to playback was not genotype-dependent and emitted response calls were divergent in meaning. This is the first report of these socially relevant responses using a genetic model of ASD. A comprehensive and empirical analysis of vigorous play during juvenile reciprocal social interactions further revealed fewer bouts and reduced durations of time spent playing by multiple key parameters, including reduced anogenital sniffing and allogrooming. We further discovered that male null Shank3-deficient pups emitted fewer isolation-induced USV than Shank3 wildtype controls. Postnatal whole brain anatomical phenotyping was applied to visualize anatomical substrates that underlie developmental phenotypes. The data presented here lend support for the important role of Shank3 in social communication, the core symptom domain of ASD. By increasing the number of in vivo functional outcome measures, we improved the likelihood for identifying and moving forward with medical interventions. Autism Res 2018, 11: 587-601. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Clinically relevant outcomes are required to demonstrate the utility of therapeutics. We introduce findings in a rat model, and assess the impact of mutations in Shank3, an autism risk gene. We found that males with deficient expression of Shank3 did not demonstrate typical responses in a bi-directional social communication test and that social interaction was lower on key parameters. Outcome measures reported herein extend earlier results in mice and capture responses to acoustic calls, which is analogous to measuring receptive and expressive communication. En ligne : http://dx.doi.org/10.1002/aur.1925 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=358
in Autism Research > 11-4 (April 2018) . - p.587-601[article] Developmental social communication deficits in the Shank3 rat model of phelan-mcdermid syndrome and autism spectrum disorder [Texte imprimé et/ou numérique] / Elizabeth L. BERG, Auteur ; N. A. COPPING, Auteur ; J. K. RIVERA, Auteur ; M. C. PRIDE, Auteur ; Milo CAREAGA, Auteur ; M. D. BAUMAN, Auteur ; Robert F. BERMAN, Auteur ; P. J. LEIN, Auteur ; Hala HARONY-NICOLAS, Auteur ; Joseph D. BUXBAUM, Auteur ; J. ELLEGOOD, Auteur ; J. P. LERCH, Auteur ; M. WOHR, Auteur ; J. L. SILVERMAN, Auteur . - p.587-601.
Langues : Anglais (eng)
in Autism Research > 11-4 (April 2018) . - p.587-601
Mots-clés : Phelan McDermid Syndrome animal model autism behavior neurodevelopment shank social synapse Index. décimale : PER Périodiques Résumé : Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions. We report, for the first time, a call and response acoustic playback assay of bidirectional social communication in juvenile Shank3 rats. Interestingly, we found that Shank3-deficient null males did not demonstrate the enhanced social approach behavior typically exhibited following playback of pro-social USV. Concomitantly, we discovered that emission of USV in response to playback was not genotype-dependent and emitted response calls were divergent in meaning. This is the first report of these socially relevant responses using a genetic model of ASD. A comprehensive and empirical analysis of vigorous play during juvenile reciprocal social interactions further revealed fewer bouts and reduced durations of time spent playing by multiple key parameters, including reduced anogenital sniffing and allogrooming. We further discovered that male null Shank3-deficient pups emitted fewer isolation-induced USV than Shank3 wildtype controls. Postnatal whole brain anatomical phenotyping was applied to visualize anatomical substrates that underlie developmental phenotypes. The data presented here lend support for the important role of Shank3 in social communication, the core symptom domain of ASD. By increasing the number of in vivo functional outcome measures, we improved the likelihood for identifying and moving forward with medical interventions. Autism Res 2018, 11: 587-601. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Clinically relevant outcomes are required to demonstrate the utility of therapeutics. We introduce findings in a rat model, and assess the impact of mutations in Shank3, an autism risk gene. We found that males with deficient expression of Shank3 did not demonstrate typical responses in a bi-directional social communication test and that social interaction was lower on key parameters. Outcome measures reported herein extend earlier results in mice and capture responses to acoustic calls, which is analogous to measuring receptive and expressive communication. En ligne : http://dx.doi.org/10.1002/aur.1925 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=358 Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism / S. C. DHAMNE in Molecular Autism, 8 (2017)
[article]
Titre : Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism Type de document : Texte imprimé et/ou numérique Auteurs : S. C. DHAMNE, Auteur ; J. L. SILVERMAN, Auteur ; C. E. SUPER, Auteur ; S. H. T. LAMMERS, Auteur ; M. Q. HAMEED, Auteur ; M. E. MODI, Auteur ; N. A. COPPING, Auteur ; M. C. PRIDE, Auteur ; D. G. SMITH, Auteur ; A. ROTENBERG, Auteur ; J. N. CRAWLEY, Auteur ; M. SAHIN, Auteur Article en page(s) : 26p. Langues : Anglais (eng) Mots-clés : Anxiety Autism Gamma oscillations Pentylenetetrazol Repetitive behavior Shank3B Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery. En ligne : http://dx.doi.org/10.1186/s13229-017-0142-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 26p.[article] Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism [Texte imprimé et/ou numérique] / S. C. DHAMNE, Auteur ; J. L. SILVERMAN, Auteur ; C. E. SUPER, Auteur ; S. H. T. LAMMERS, Auteur ; M. Q. HAMEED, Auteur ; M. E. MODI, Auteur ; N. A. COPPING, Auteur ; M. C. PRIDE, Auteur ; D. G. SMITH, Auteur ; A. ROTENBERG, Auteur ; J. N. CRAWLEY, Auteur ; M. SAHIN, Auteur . - 26p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 26p.
Mots-clés : Anxiety Autism Gamma oscillations Pentylenetetrazol Repetitive behavior Shank3B Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery. En ligne : http://dx.doi.org/10.1186/s13229-017-0142-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330