Abnormal electrophysiological phenotypes and sleep deficits in a mouse model of Angelman Syndrome / Nycole A. COPPING in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 9p. Titre : Abnormal electrophysiological phenotypes and sleep deficits in a mouse model of Angelman Syndrome Type de document : texte imprimé Auteurs : Nycole A. COPPING, Auteur ; Jill L. SILVERMAN, Auteur Article en page(s) : 9p. Langues : Anglais (eng) Mots-clés : Angelman Syndrome  Behavior  Genetics  Mouse models  Seizures  Sleep  Spindles  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal-specific loss of expression of UBE3A (ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (> 80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS. METHODS: We used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported in Ube3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light-dark cycles, sleep stages and sleep spindles in Ube3a-del and WT mice. RESULTS: Ube3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated that Ube3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model. LIMITATIONS: This study was limited to the exon 2 deletion mouse model, and future work will investigate the rat model of AS, containing a complete Ube3a deletion and pair EEG with behavior. CONCLUSIONS: Our data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing. En ligne : http://dx.doi.org/10.1186/s13229-021-00416-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442 [article] Abnormal electrophysiological phenotypes and sleep deficits in a mouse model of Angelman Syndrome [texte imprimé] / Nycole A. COPPING, Auteur ; Jill L. SILVERMAN, Auteur . - 9p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 9p. Mots-clés : Angelman Syndrome  Behavior  Genetics  Mouse models  Seizures  Sleep  Spindles  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal-specific loss of expression of UBE3A (ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (> 80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS. METHODS: We used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported in Ube3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light-dark cycles, sleep stages and sleep spindles in Ube3a-del and WT mice. RESULTS: Ube3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated that Ube3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model. LIMITATIONS: This study was limited to the exon 2 deletion mouse model, and future work will investigate the rat model of AS, containing a complete Ube3a deletion and pair EEG with behavior. CONCLUSIONS: Our data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing. En ligne : http://dx.doi.org/10.1186/s13229-021-00416-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442

Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome / Timothy A. FENTON in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome Type de document : texte imprimé Auteurs : Timothy A. FENTON, Auteur ; Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Jill L. SILVERMAN, Auteur Langues : Anglais (eng) Mots-clés : Animals  Lovastatin/pharmacology/administration & dosage  Angelman Syndrome/drug therapy/physiopathology/genetics  Disease Models, Animal  Mice  Gait/drug effects  Male  Cognition/drug effects  Female  Behavior, Animal/drug effects  Mice, Inbred C57BL  Ubiquitin-Protein Ligases/genetics  Motor Activity/drug effects  Angelman syndrome  Behavior  Gait  Lovastatin  Neurodevelopmental disorder  UBE3A  reviewed and approved by the UC Davis IACUC on April 20, 2023. Active protocols  are reviewed annually. Title: Novel Testing of Therapeutics for Angelman  Syndrome. Principal Investigator: Jill L. Silverman Protocol #: 23384  Institution: University of California, Davis This institution is accredited by  the Association for Assessment and Accreditation of Laboratory Animal Care,  International (AAALAC). This institution has an Animal Welfare Assurance on file  with the Office of Laboratory Animal Welfare (OLAW). The Assurance Number is  D16-00272 (A3433-01). The IACUC is constituted in accordance with U.S. Public  Health Service (PHS) Animal Welfare Policy and includes a member of the public  and a non-scientist. Consent for publication: FAST, the MIND Institute and the  NIH/NICHD IDDRC consent for the data presented herein to be publishable.  Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and intellectual disabilities (IDs). One NDD, associated with ASD and ID, is Angelman Syndrome (AS). AS is a rare genetic NDD for which there is currently no cure nor effective therapeutics. The genetic cause is known to be the loss of expression from the maternal allele of ubiquitin protein ligase E3A (UBE3A). The Ube3a maternal deletion mouse model of AS reliably demonstrates behavioral phenotypes of relevance to AS and therefore offers a suitable in vivo system in which to test potential therapeutics, with construct and face validity. Successes in reducing hyperexcitability and epileptogenesis have been reported in an AS model following acute treatment with lovastatin, an ERK inhibitor by reducing seizure threshold and percentage of mice exhibiting seizures. Since there has been literature reporting disruption of the ERK signaling pathway in AS, we chose to evaluate the effects of acute lovastatin administration in a tailored set of translationally relevant behavioral assays in a mouse model of AS. Unexpectedly, deleterious effects of sedation were observed in wildtype (WT), age matched littermate control mice and despite a baseline hypolocomotive phenotype in AS mice, even further reductions in exploratory activity, were observed post-acute lovastatin treatment. Limitations of this work include that chronic lower dose regimens, more akin to drug administration in humans were beyond the scope of this work, and may have produced a more favorable impact of lovastatin administration over single acute high doses. In addition, lovastatin's effects were not assessed in younger subjects, since our study focused exclusively on adult functional outcomes. Metrics of gait, as well as motor coordination and motor learning in rotarod, previously observed to be impaired in AS mice, were not improved by lovastatin treatment. Finally, cognition by novel object recognition task was worsened in WT controls and not improved in AS, following lovastatin administration. In conclusion, lovastatin did not indicate any major improvement to AS symptoms, and in fact, worsened behavioral outcomes in the WT control groups. Therefore, despite its attractive low toxicity, immediate availability, and low cost of the drug, further investigation for clinical study is unwarranted given the results presented herein. En ligne : https://dx.doi.org/10.1186/s11689-025-09616-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome [texte imprimé] / Timothy A. FENTON, Auteur ; Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Jill L. SILVERMAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Animals  Lovastatin/pharmacology/administration & dosage  Angelman Syndrome/drug therapy/physiopathology/genetics  Disease Models, Animal  Mice  Gait/drug effects  Male  Cognition/drug effects  Female  Behavior, Animal/drug effects  Mice, Inbred C57BL  Ubiquitin-Protein Ligases/genetics  Motor Activity/drug effects  Angelman syndrome  Behavior  Gait  Lovastatin  Neurodevelopmental disorder  UBE3A  reviewed and approved by the UC Davis IACUC on April 20, 2023. Active protocols  are reviewed annually. Title: Novel Testing of Therapeutics for Angelman  Syndrome. Principal Investigator: Jill L. Silverman Protocol #: 23384  Institution: University of California, Davis This institution is accredited by  the Association for Assessment and Accreditation of Laboratory Animal Care,  International (AAALAC). This institution has an Animal Welfare Assurance on file  with the Office of Laboratory Animal Welfare (OLAW). The Assurance Number is  D16-00272 (A3433-01). The IACUC is constituted in accordance with U.S. Public  Health Service (PHS) Animal Welfare Policy and includes a member of the public  and a non-scientist. Consent for publication: FAST, the MIND Institute and the  NIH/NICHD IDDRC consent for the data presented herein to be publishable.  Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and intellectual disabilities (IDs). One NDD, associated with ASD and ID, is Angelman Syndrome (AS). AS is a rare genetic NDD for which there is currently no cure nor effective therapeutics. The genetic cause is known to be the loss of expression from the maternal allele of ubiquitin protein ligase E3A (UBE3A). The Ube3a maternal deletion mouse model of AS reliably demonstrates behavioral phenotypes of relevance to AS and therefore offers a suitable in vivo system in which to test potential therapeutics, with construct and face validity. Successes in reducing hyperexcitability and epileptogenesis have been reported in an AS model following acute treatment with lovastatin, an ERK inhibitor by reducing seizure threshold and percentage of mice exhibiting seizures. Since there has been literature reporting disruption of the ERK signaling pathway in AS, we chose to evaluate the effects of acute lovastatin administration in a tailored set of translationally relevant behavioral assays in a mouse model of AS. Unexpectedly, deleterious effects of sedation were observed in wildtype (WT), age matched littermate control mice and despite a baseline hypolocomotive phenotype in AS mice, even further reductions in exploratory activity, were observed post-acute lovastatin treatment. Limitations of this work include that chronic lower dose regimens, more akin to drug administration in humans were beyond the scope of this work, and may have produced a more favorable impact of lovastatin administration over single acute high doses. In addition, lovastatin's effects were not assessed in younger subjects, since our study focused exclusively on adult functional outcomes. Metrics of gait, as well as motor coordination and motor learning in rotarod, previously observed to be impaired in AS mice, were not improved by lovastatin treatment. Finally, cognition by novel object recognition task was worsened in WT controls and not improved in AS, following lovastatin administration. In conclusion, lovastatin did not indicate any major improvement to AS symptoms, and in fact, worsened behavioral outcomes in the WT control groups. Therefore, despite its attractive low toxicity, immediate availability, and low cost of the drug, further investigation for clinical study is unwarranted given the results presented herein. En ligne : https://dx.doi.org/10.1186/s11689-025-09616-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Behavioral Evaluation of Genetic Mouse Models of Autism / Mu YANG

Public ISBD in Autism Spectrum Disorders / David G. AMARAL Titre : Behavioral Evaluation of Genetic Mouse Models of Autism Type de document : texte imprimé Auteurs : Mu YANG, Auteur ; Maria Luisa SCATTONI, Auteur ; Kathryn K. CHADMAN, Auteur ; Jill L. SILVERMAN, Auteur ; Jacqueline N. CRAWLEY, Auteur Année de publication : 2011 Importance : p.906-934 Langues : Anglais (eng) Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=140 in Autism Spectrum Disorders / David G. AMARAL Behavioral Evaluation of Genetic Mouse Models of Autism [texte imprimé] / Mu YANG, Auteur ; Maria Luisa SCATTONI, Auteur ; Kathryn K. CHADMAN, Auteur ; Jill L. SILVERMAN, Auteur ; Jacqueline N. CRAWLEY, Auteur . - 2011 . - p.906-934. Langues : Anglais (eng) Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=140

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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)  

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 Auteurs : Elizabeth L. BERG, Auteur ; Nycole A. COPPING, Auteur ; Josef K. RIVERA, Auteur ; Michael C. PRIDE, Auteur ; Milo CAREAGA, Auteur ; Melissa D. BAUMAN, Auteur ; Robert F. BERMAN, Auteur ; Pamela J. LEIN, Auteur ; Hala HARONY-NICOLAS, Auteur ; Joseph D. BUXBAUM, Auteur ; Jacob ELLEGOOD, Auteur ; Jason P. LERCH, Auteur ; M. WOHR, Auteur ; Jill 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] / Elizabeth L. BERG, Auteur ; Nycole A. COPPING, Auteur ; Josef K. RIVERA, Auteur ; Michael C. PRIDE, Auteur ; Milo CAREAGA, Auteur ; Melissa D. BAUMAN, Auteur ; Robert F. BERMAN, Auteur ; Pamela J. LEIN, Auteur ; Hala HARONY-NICOLAS, Auteur ; Joseph D. BUXBAUM, Auteur ; Jacob ELLEGOOD, Auteur ; Jason P. LERCH, Auteur ; M. WOHR, Auteur ; Jill 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

Gait as a quantitative translational outcome measure in Angelman syndrome / Stela P. PETKOVA in Autism Research, 15-5 (May 2022)  

Public ISBD [article]  inAutism Research > 15-5 (May 2022) . - p.821-833 Titre : Gait as a quantitative translational outcome measure in Angelman syndrome Type de document : texte imprimé Auteurs : Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Elizabeth L. BERG, Auteur ; Timothy A. FENTON, Auteur ; Jessica DUIS, Auteur ; Jill L. SILVERMAN, Auteur Article en page(s) : p.821-833 Langues : Anglais (eng) Mots-clés : Angelman Syndrome/genetics  Animals  Autism Spectrum Disorder  Disease Models, Animal  Gait/physiology  Humans  Mice  Movement Disorders  Muscle Hypotonia  Outcome Assessment, Health Care  Angelman syndrome  animal models  autism  behavior  gait  genetics  longitudinal  motor  mouse models  neurodevelopment Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions. En ligne : http://dx.doi.org/10.1002/aur.2697 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 [article] Gait as a quantitative translational outcome measure in Angelman syndrome [texte imprimé] / Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Elizabeth L. BERG, Auteur ; Timothy A. FENTON, Auteur ; Jessica DUIS, Auteur ; Jill L. SILVERMAN, Auteur . - p.821-833. Langues : Anglais (eng) in Autism Research > 15-5 (May 2022) . - p.821-833 Mots-clés : Angelman Syndrome/genetics  Animals  Autism Spectrum Disorder  Disease Models, Animal  Gait/physiology  Humans  Mice  Movement Disorders  Muscle Hypotonia  Outcome Assessment, Health Care  Angelman syndrome  animal models  autism  behavior  gait  genetics  longitudinal  motor  mouse models  neurodevelopment Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions. En ligne : http://dx.doi.org/10.1002/aur.2697 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473

Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion / Andie DODGE in Autism Research, 13-3 (March 2020)  

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Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication / Ozlem BOZDAGI in Molecular Autism, (December 2010)  

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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)  

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

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

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Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos / Elizabeth L. BERG in Journal of Neurodevelopmental Disorders, 12 (2020)  

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