10 recherche sur le mot-clé 'Rat'

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

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos Type de document : texte imprimé Auteurs : Elizabeth L. BERG, Auteur ; Tianna M. CHING, Auteur ; Donald A. BRUUN, Auteur ; Josef K. RIVERA, Auteur ; Milo CAREAGA, Auteur ; Jacob ELLEGOOD, Auteur ; Jason P. LERCH, Auteur ; Markus WÖHR, Auteur ; Pamela J. LEIN, Auteur ; Jill L. SILVERMAN, Auteur Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder  Brain  Chlorpyrifos/toxicity  Female  Male  Pregnancy  Prenatal Exposure Delayed Effects  Rats  Rats, Sprague-Dawley  United States  Animal models  Autism  Behavior  Chlorpyrifos  Imaging  Neurodevelopment  Pesticides  Rat  Social  Toxicology  Usv  Vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest that children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of intellectual delay or disability, ADHD, or ASD. METHODS: We tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes (i.e., deficits in social communication and repetitive, restricted behavior). Male and female rat pups were exposed to CPF at 0.1, 0.3, or 1.0 mg/kg (s.c.) from postnatal days 1-4. RESULTS: These CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF-exposed rats and the corresponding vehicle controls using strict false discovery correction; however, there were interesting trends in females in the 0.3 mg/kg dose group. CONCLUSIONS: This work generated and characterized a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in the brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered. En ligne : https://dx.doi.org/10.1186/s11689-020-09342-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos [texte imprimé] / Elizabeth L. BERG, Auteur ; Tianna M. CHING, Auteur ; Donald A. BRUUN, Auteur ; Josef K. RIVERA, Auteur ; Milo CAREAGA, Auteur ; Jacob ELLEGOOD, Auteur ; Jason P. LERCH, Auteur ; Markus WÖHR, Auteur ; Pamela J. LEIN, Auteur ; Jill L. SILVERMAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Animals  Autism Spectrum Disorder  Brain  Chlorpyrifos/toxicity  Female  Male  Pregnancy  Prenatal Exposure Delayed Effects  Rats  Rats, Sprague-Dawley  United States  Animal models  Autism  Behavior  Chlorpyrifos  Imaging  Neurodevelopment  Pesticides  Rat  Social  Toxicology  Usv  Vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest that children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of intellectual delay or disability, ADHD, or ASD. METHODS: We tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes (i.e., deficits in social communication and repetitive, restricted behavior). Male and female rat pups were exposed to CPF at 0.1, 0.3, or 1.0 mg/kg (s.c.) from postnatal days 1-4. RESULTS: These CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF-exposed rats and the corresponding vehicle controls using strict false discovery correction; however, there were interesting trends in females in the 0.3 mg/kg dose group. CONCLUSIONS: This work generated and characterized a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in the brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered. En ligne : https://dx.doi.org/10.1186/s11689-020-09342-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder / Mohammed Sarfaraz NAWAZ ; Peter C. KIND ; Michael A. COUSIN in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 26 Titre : Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder Type de document : texte imprimé Auteurs : Mohammed Sarfaraz NAWAZ, Auteur ; Peter C. KIND, Auteur ; Michael A. COUSIN, Auteur Article en page(s) : 26 Langues : Anglais (eng) Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder [texte imprimé] / Mohammed Sarfaraz NAWAZ, Auteur ; Peter C. KIND, Auteur ; Michael A. COUSIN, Auteur . - 26. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 26 Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder / Laura SIMÕES DE OLIVEIRA in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 28p. Titre : Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder Type de document : texte imprimé Auteurs : Laura SIMÕES DE OLIVEIRA, Auteur ; Heather E. O'LEARY, Auteur ; Sarfaraz NAWAZ, Auteur ; Rita LOUREIRO, Auteur ; Elizabeth C. DAVENPORT, Auteur ; Paul S. BAXTER, Auteur ; Susana R. LOUROS, Auteur ; Owen R. DANDO, Auteur ; Emma PERKINS, Auteur ; Julien PELTIER, Auteur ; Matthias TROST, Auteur ; Emily K. OSTERWEIL, Auteur ; Giles E. HARDINGHAM, Auteur ; Michael A. COUSIN, Auteur ; Sumantra CHATTARJI, Auteur ; Sam A. BOOKER, Auteur ; Timothy A. BENKE, Auteur ; David J.A. WYLLIE, Auteur ; Peter C. KIND, Auteur Article en page(s) : 28p. Langues : Anglais (eng) Mots-clés : Animals  Male  Rats  CA1 Region, Hippocampal/metabolism/pathology/physiopathology  Disease Models, Animal  Epileptic Syndromes/genetics/metabolism  Excitatory Postsynaptic Potentials  Genetic Diseases, X-Linked/genetics/metabolism/physiopathology  Hippocampus/metabolism  Long-Term Potentiation  Protein Serine-Threonine Kinases/metabolism/genetics  Pyramidal Cells/metabolism/pathology  Receptors, AMPA/metabolism/genetics  Receptors, N-Methyl-D-Aspartate/metabolism/genetics  Spasms, Infantile/genetics/metabolism  Synapses/metabolism  AMPA receptor  Cdkl5  NMDA receptor  hippocampus  intrinsic properties  rat  synaptic plasticity Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5(-/y) rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5(-/y) rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5(-/y) rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca(2+) permeable AMPA receptor mediated currents are unchanged in Cdkl5(-/y) rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD. En ligne : https://dx.doi.org/10.1186/s13229-024-00601-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder [texte imprimé] / Laura SIMÕES DE OLIVEIRA, Auteur ; Heather E. O'LEARY, Auteur ; Sarfaraz NAWAZ, Auteur ; Rita LOUREIRO, Auteur ; Elizabeth C. DAVENPORT, Auteur ; Paul S. BAXTER, Auteur ; Susana R. LOUROS, Auteur ; Owen R. DANDO, Auteur ; Emma PERKINS, Auteur ; Julien PELTIER, Auteur ; Matthias TROST, Auteur ; Emily K. OSTERWEIL, Auteur ; Giles E. HARDINGHAM, Auteur ; Michael A. COUSIN, Auteur ; Sumantra CHATTARJI, Auteur ; Sam A. BOOKER, Auteur ; Timothy A. BENKE, Auteur ; David J.A. WYLLIE, Auteur ; Peter C. KIND, Auteur . - 28p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 28p. Mots-clés : Animals  Male  Rats  CA1 Region, Hippocampal/metabolism/pathology/physiopathology  Disease Models, Animal  Epileptic Syndromes/genetics/metabolism  Excitatory Postsynaptic Potentials  Genetic Diseases, X-Linked/genetics/metabolism/physiopathology  Hippocampus/metabolism  Long-Term Potentiation  Protein Serine-Threonine Kinases/metabolism/genetics  Pyramidal Cells/metabolism/pathology  Receptors, AMPA/metabolism/genetics  Receptors, N-Methyl-D-Aspartate/metabolism/genetics  Spasms, Infantile/genetics/metabolism  Synapses/metabolism  AMPA receptor  Cdkl5  NMDA receptor  hippocampus  intrinsic properties  rat  synaptic plasticity Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5(-/y) rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5(-/y) rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5(-/y) rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca(2+) permeable AMPA receptor mediated currents are unchanged in Cdkl5(-/y) rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD. En ligne : https://dx.doi.org/10.1186/s13229-024-00601-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

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

Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity / Andie DODGE in Autism Research, 14-4 (April 2021)  

Public ISBD [article]  inAutism Research > 14-4 (April 2021) . - p.645-655 Titre : Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity Type de document : texte imprimé Auteurs : Andie DODGE, Auteur ; Jonathan WILLMAN, Auteur ; Matthew WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Nicole K. MORRILL, Auteur ; Kristina LAMENS, Auteur ; Hayden GREENE, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur Article en page(s) : p.645-655 Langues : Anglais (eng) Mots-clés : Angelman syndrome  Csf  E6ap  Ube3a  rat model Index. décimale : PER Périodiques Résumé : Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2475 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443 [article] Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity [texte imprimé] / Andie DODGE, Auteur ; Jonathan WILLMAN, Auteur ; Matthew WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Nicole K. MORRILL, Auteur ; Kristina LAMENS, Auteur ; Hayden GREENE, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur . - p.645-655. Langues : Anglais (eng) in Autism Research > 14-4 (April 2021) . - p.645-655 Mots-clés : Angelman syndrome  Csf  E6ap  Ube3a  rat model Index. décimale : PER Périodiques Résumé : Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2475 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443

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