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

Public ISBD [article]  inAutism Research > 13-3 (March 2020) . - p.397-409 Titre : Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion Type de document : texte imprimé Auteurs : Andie DODGE, Auteur ; Melinda M. PETERS, Auteur ; Hayden E. GREENE, Auteur ; Clifton DIETRICK, Auteur ; Robert BOTELHO, Auteur ; Diana CHUNG, Auteur ; Jonathan WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Stephanie CIARLONE, Auteur ; Siddharth G. KAMATH, Auteur ; Pavel HOUDEK, Auteur ; Alena SUMOVA, Auteur ; Anne E. ANDERSON, Auteur ; Scott V. DINDOT, Auteur ; Elizabeth L. BERG, Auteur ; Henriette O'GEEN, Auteur ; David J. SEGAL, Auteur ; Jill L. SILVERMAN, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur Article en page(s) : p.397-409 Langues : Anglais (eng) Mots-clés : Angelman syndrome  E6ap  Ube3a  cognitive deficits  rat model Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. (c) 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. En ligne : http://dx.doi.org/10.1002/aur.2267 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=421 [article] Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion [texte imprimé] / Andie DODGE, Auteur ; Melinda M. PETERS, Auteur ; Hayden E. GREENE, Auteur ; Clifton DIETRICK, Auteur ; Robert BOTELHO, Auteur ; Diana CHUNG, Auteur ; Jonathan WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Stephanie CIARLONE, Auteur ; Siddharth G. KAMATH, Auteur ; Pavel HOUDEK, Auteur ; Alena SUMOVA, Auteur ; Anne E. ANDERSON, Auteur ; Scott V. DINDOT, Auteur ; Elizabeth L. BERG, Auteur ; Henriette O'GEEN, Auteur ; David J. SEGAL, Auteur ; Jill L. SILVERMAN, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur . - p.397-409. Langues : Anglais (eng) in Autism Research > 13-3 (March 2020) . - p.397-409 Mots-clés : Angelman syndrome  E6ap  Ube3a  cognitive deficits  rat model Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. (c) 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. En ligne : http://dx.doi.org/10.1002/aur.2267 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=421

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 Auteurs : Elizabeth L. BERG, Auteur ; Stela P. PETKOVA, Auteur ; Heather A. BORN, Auteur ; Anna ADHIKARI, Auteur ; Anne E. ANDERSON, Auteur ; Jill 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] / Elizabeth L. BERG, Auteur ; Stela P. PETKOVA, Auteur ; Heather A. BORN, Auteur ; Anna ADHIKARI, Auteur ; Anne E. ANDERSON, Auteur ; Jill 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

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