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)  

Public ISBD [article]  inAutism Research > 11-4 (April 2018) . - p.587-601 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 [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

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome / Elizabeth L. BERG in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 59 p. Titre : Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Elizabeth L. BERG, Auteur ; S. P. PETKOVA, Auteur ; H. A. BORN, Auteur ; A. ADHIKARI, Auteur ; A. E. ANDERSON, Auteur ; J. L. SILVERMAN, Auteur Article en page(s) : 59 p. Langues : Anglais (eng) Mots-clés : Angelman Syndrome  Behavior  Eeg  Igf  Insulin-like growth factor  Mouse model  Rat model  Ube3a  Ubiquitin Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems. METHODS: We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes. RESULTS: Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition. LIMITATIONS: The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy. CONCLUSIONS: Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS. En ligne : http://dx.doi.org/10.1186/s13229-021-00467-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome [Texte imprimé et/ou numérique] / Elizabeth L. BERG, Auteur ; S. P. PETKOVA, Auteur ; H. A. BORN, Auteur ; A. ADHIKARI, Auteur ; A. E. ANDERSON, Auteur ; J. L. SILVERMAN, Auteur . - 59 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 59 p. Mots-clés : Angelman Syndrome  Behavior  Eeg  Igf  Insulin-like growth factor  Mouse model  Rat model  Ube3a  Ubiquitin Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems. METHODS: We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes. RESULTS: Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition. LIMITATIONS: The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy. CONCLUSIONS: Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS. En ligne : http://dx.doi.org/10.1186/s13229-021-00467-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development / J. ELLEGOOD in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 25 p. Titre : Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development Type de document : Texte imprimé et/ou numérique Auteurs : J. ELLEGOOD, Auteur ; S. P. PETKOVA, Auteur ; A. KINMAN, Auteur ; L. R. QIU, Auteur ; A. ADHIKARI, Auteur ; A. A. WADE, Auteur ; D. FERNANDES, Auteur ; Z. LINDENMAIER, Auteur ; A. CREIGHTON, Auteur ; L. M. J. NUTTER, Auteur ; A. S. NORD, Auteur ; J. L. SILVERMAN, Auteur ; J. P. LERCH, Auteur Article en page(s) : 25 p. Langues : Anglais (eng) Mots-clés : Animals  Behavior, Animal  Brain/diagnostic imaging/growth & development  Exploratory Behavior  Fear  Female  Gait  Haploinsufficiency  Learning  Magnetic Resonance Imaging  Male  Mice, Mutant Strains  Motor Skills  Neurodevelopmental Disorders/diagnostic imaging/psychology  Recognition, Psychology  Social Behavior  Transcription Factors/genetics/metabolism  Vocalization, Animal  Arid1b  Autism  Behavior  Coffin–Siris syndrome  Magnetic resonance imaging  Mouse Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. METHODS: A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. RESULTS: We validated decreased Arid1b mRNA and protein in Arid1b(+/-) mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b(+/-) cerebellum. During neonatal development, Arid1b(+/-) mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b(+/-) mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b(+/-) mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b(+/-) mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. LIMITATIONS: The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. CONCLUSIONS: This study represents a full validation and investigation of a novel model of Arid1b(+/-) haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs. En ligne : http://dx.doi.org/10.1186/s13229-021-00432-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development [Texte imprimé et/ou numérique] / J. ELLEGOOD, Auteur ; S. P. PETKOVA, Auteur ; A. KINMAN, Auteur ; L. R. QIU, Auteur ; A. ADHIKARI, Auteur ; A. A. WADE, Auteur ; D. FERNANDES, Auteur ; Z. LINDENMAIER, Auteur ; A. CREIGHTON, Auteur ; L. M. J. NUTTER, Auteur ; A. S. NORD, Auteur ; J. L. SILVERMAN, Auteur ; J. P. LERCH, Auteur . - 25 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 25 p. Mots-clés : Animals  Behavior, Animal  Brain/diagnostic imaging/growth & development  Exploratory Behavior  Fear  Female  Gait  Haploinsufficiency  Learning  Magnetic Resonance Imaging  Male  Mice, Mutant Strains  Motor Skills  Neurodevelopmental Disorders/diagnostic imaging/psychology  Recognition, Psychology  Social Behavior  Transcription Factors/genetics/metabolism  Vocalization, Animal  Arid1b  Autism  Behavior  Coffin–Siris syndrome  Magnetic resonance imaging  Mouse Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. METHODS: A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. RESULTS: We validated decreased Arid1b mRNA and protein in Arid1b(+/-) mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b(+/-) cerebellum. During neonatal development, Arid1b(+/-) mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b(+/-) mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b(+/-) mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b(+/-) mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. LIMITATIONS: The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. CONCLUSIONS: This study represents a full validation and investigation of a novel model of Arid1b(+/-) haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs. En ligne : http://dx.doi.org/10.1186/s13229-021-00432-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

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

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