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

Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome / Robert F. BERMAN in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.25 Titre : Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Robert F. BERMAN, Auteur ; R. A. BUIJSEN, Auteur ; K. USDIN, Auteur ; E. PINTADO, Auteur ; F. KOOY, Auteur ; D. PRETTO, Auteur ; I. N. PESSAH, Auteur ; D. L. NELSON, Auteur ; Z. ZALEWSKI, Auteur ; N. CHARLET-BERGEURAND, Auteur ; R. WILLEMSEN, Auteur ; R. K. HUKEMA, Auteur Article en page(s) : p.25 Langues : Anglais (eng) Mots-clés : CGG trinucleotide repeat  Fmr1  Fmrp  Fxtas  Fragile X premutation  Intranuclear inclusions  Mouse models  RNA toxicity Index. décimale : PER Périodiques Résumé : Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered. En ligne : http://dx.doi.org/10.1186/1866-1955-6-25 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346 [article] Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome [Texte imprimé et/ou numérique] / Robert F. BERMAN, Auteur ; R. A. BUIJSEN, Auteur ; K. USDIN, Auteur ; E. PINTADO, Auteur ; F. KOOY, Auteur ; D. PRETTO, Auteur ; I. N. PESSAH, Auteur ; D. L. NELSON, Auteur ; Z. ZALEWSKI, Auteur ; N. CHARLET-BERGEURAND, Auteur ; R. WILLEMSEN, Auteur ; R. K. HUKEMA, Auteur . - p.25. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.25 Mots-clés : CGG trinucleotide repeat  Fmr1  Fmrp  Fxtas  Fragile X premutation  Intranuclear inclusions  Mouse models  RNA toxicity Index. décimale : PER Périodiques Résumé : Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered. En ligne : http://dx.doi.org/10.1186/1866-1955-6-25 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346

Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome / Claudia M. GRECO in Molecular Autism, (February 2011)  

Public ISBD [article]  inMolecular Autism > (February 2011) . - 13 p. Titre : Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Claudia M. GRECO, Auteur ; Celestine S. NAVARRO, Auteur ; Michael R. HUNSAKER, Auteur ; Izumi MAEZAWA, Auteur ; John F. SHULER, Auteur ; Flora TASSONE, Auteur ; Mary DELANY, Auteur ; Jacky W. AU, Auteur ; Robert F. BERMAN, Auteur ; Lee-Way JIN, Auteur ; Cynthia M. SCHUMANN, Auteur ; Paul J. HAGERMAN, Auteur ; Randi J. HAGERMAN, Auteur Année de publication : 2011 Article en page(s) : 13 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Methods Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Results Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Conclusions Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS. En ligne : http://dx.doi.org/10.1186/2040-2392-2-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=121 [article] Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome [Texte imprimé et/ou numérique] / Claudia M. GRECO, Auteur ; Celestine S. NAVARRO, Auteur ; Michael R. HUNSAKER, Auteur ; Izumi MAEZAWA, Auteur ; John F. SHULER, Auteur ; Flora TASSONE, Auteur ; Mary DELANY, Auteur ; Jacky W. AU, Auteur ; Robert F. BERMAN, Auteur ; Lee-Way JIN, Auteur ; Cynthia M. SCHUMANN, Auteur ; Paul J. HAGERMAN, Auteur ; Randi J. HAGERMAN, Auteur . - 2011 . - 13 p. Langues : Anglais (eng) in Molecular Autism > (February 2011) . - 13 p. Index. décimale : PER Périodiques Résumé : Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Methods Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Results Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Conclusions Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS. En ligne : http://dx.doi.org/10.1186/2040-2392-2-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=121

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