Hypothesis-driven investigations of diverse pharmacological targets in two mouse models of autism / M. A. RHINE in Autism Research, 12-3 (March 2019)  

Public ISBD [article]  inAutism Research > 12-3 (March 2019) . - p.401-421 Titre : Hypothesis-driven investigations of diverse pharmacological targets in two mouse models of autism Type de document : Texte imprimé et/ou numérique Auteurs : M. A. RHINE, Auteur ; J. M. PARROTT, Auteur ; M. N. SCHULTZ, Auteur ; T. M. KAZDOBA, Auteur ; J. N. CRAWLEY, Auteur Article en page(s) : p.401-421 Langues : Anglais (eng) Mots-clés : Gaba  Trkb  autism  cognitive  medicine  mice  preclinical  repetitive  social Index. décimale : PER Périodiques Résumé : Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan-McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA-A receptor agonist gaboxadol significantly reduced repetitive self-grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8-DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d-cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019, 12: 401-421 (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA-A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism. En ligne : http://dx.doi.org/10.1002/aur.2066 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=387 [article] Hypothesis-driven investigations of diverse pharmacological targets in two mouse models of autism [Texte imprimé et/ou numérique] / M. A. RHINE, Auteur ; J. M. PARROTT, Auteur ; M. N. SCHULTZ, Auteur ; T. M. KAZDOBA, Auteur ; J. N. CRAWLEY, Auteur . - p.401-421. Langues : Anglais (eng) in Autism Research > 12-3 (March 2019) . - p.401-421 Mots-clés : Gaba  Trkb  autism  cognitive  medicine  mice  preclinical  repetitive  social Index. décimale : PER Périodiques Résumé : Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan-McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA-A receptor agonist gaboxadol significantly reduced repetitive self-grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8-DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d-cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019, 12: 401-421 (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA-A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism. En ligne : http://dx.doi.org/10.1002/aur.2066 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=387

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism / S. C. DHAMNE in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 26p. 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 [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

Rigor in science and science reporting: updated guidelines for submissions to Molecular Autism / Joseph D. BUXBAUM in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 6 p. Titre : Rigor in science and science reporting: updated guidelines for submissions to Molecular Autism Type de document : Texte imprimé et/ou numérique Auteurs : Joseph D. BUXBAUM, Auteur ; Simon BARON-COHEN, Auteur ; Evdokia ANAGNOSTOU, Auteur ; Chris ASHWIN, Auteur ; Catalina BETANCUR, Auteur ; Bhismadev CHAKRABARTI, Auteur ; J. N. CRAWLEY, Auteur ; R. A. HOEKSTRA, Auteur ; P. R. HOF, Auteur ; Meng-Chuan LAI, Auteur ; M. V. LOMBARDO, Auteur ; C. M. SCHUMANN, Auteur Article en page(s) : 6 p. Langues : Anglais (eng) Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s13229-018-0249-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Rigor in science and science reporting: updated guidelines for submissions to Molecular Autism [Texte imprimé et/ou numérique] / Joseph D. BUXBAUM, Auteur ; Simon BARON-COHEN, Auteur ; Evdokia ANAGNOSTOU, Auteur ; Chris ASHWIN, Auteur ; Catalina BETANCUR, Auteur ; Bhismadev CHAKRABARTI, Auteur ; J. N. CRAWLEY, Auteur ; R. A. HOEKSTRA, Auteur ; P. R. HOF, Auteur ; Meng-Chuan LAI, Auteur ; M. V. LOMBARDO, Auteur ; C. M. SCHUMANN, Auteur . - 6 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 6 p. Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s13229-018-0249-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

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