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Auteur Nathan P. DORR |
Documents disponibles écrits par cet auteur (2)
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Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions / Takeshi SAKURAI in Autism Research, 4-1 (February 2011)
[article]
Titre : Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions Type de document : Texte imprimé et/ou numérique Auteurs : Takeshi SAKURAI, Auteur ; Nathan P. DORR, Auteur ; Nagahide TAKAHASHI, Auteur ; L. Alison MCINNES, Auteur ; Gregory A. ELDER, Auteur ; Joseph D. BUXBAUM, Auteur Année de publication : 2011 Article en page(s) : p.28-39 Langues : Anglais (eng) Mots-clés : social behavior intellectual disability autism mouse model Index. décimale : PER Périodiques Résumé : Identifying genes involved in social behavior is important for autism research. Williams–Beuren syndrome (WBS) is a developmental syndrome with unique neurocognitive features, including low IQ, deficits in visuospatial and visual-motor abilities, hypersensitivity to sounds, hypersociability, and increased general anxiety. The syndrome is caused by a recurrent hemizygous deletion of the 7q11.23 region, containing about 28 genes. One of genes in the region, GTF2I, has been implicated in the hypersociability and visuospatial deficits of WBS based on genotype–phenotype correlation studies of patients with atypical deletions. In order to clarify the involvement of GTF2I in neurocognitive function, especially social behavior, we have developed and characterized Gtf2i-deficient mice. We found that homozygous deletion of Gtf2i causes lethality during embryonic development with neural tube closure defects and exencephaly, consistent with other reports. Gtf2i heterozygous animals show no gross changes in brain structure or development. Furthermore, heterozygous animals show no alterations in learning and memory, including spatial memory as assessed by the Morris water maze, but show alterations in the recognition of novel objects. Interestingly, they show increased social interaction with unfamiliar mice and do not show typical social habituation processes, reminiscent of the hypersociability observed in WBS patients. The mice do not appear to show increased anxiety, supporting a specific effect of Gtf2i on defined domains of the WBS phenotype. These data indicate that Gtf2i is involved in several aspects of embryonic development and the development of social neurocircuitry and that GTF2I haploinsufficiency could be a contributor to the hypersociability in WBS patients. En ligne : http://dx.doi.org/10.1002/aur.169 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=118
in Autism Research > 4-1 (February 2011) . - p.28-39[article] Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions [Texte imprimé et/ou numérique] / Takeshi SAKURAI, Auteur ; Nathan P. DORR, Auteur ; Nagahide TAKAHASHI, Auteur ; L. Alison MCINNES, Auteur ; Gregory A. ELDER, Auteur ; Joseph D. BUXBAUM, Auteur . - 2011 . - p.28-39.
Langues : Anglais (eng)
in Autism Research > 4-1 (February 2011) . - p.28-39
Mots-clés : social behavior intellectual disability autism mouse model Index. décimale : PER Périodiques Résumé : Identifying genes involved in social behavior is important for autism research. Williams–Beuren syndrome (WBS) is a developmental syndrome with unique neurocognitive features, including low IQ, deficits in visuospatial and visual-motor abilities, hypersensitivity to sounds, hypersociability, and increased general anxiety. The syndrome is caused by a recurrent hemizygous deletion of the 7q11.23 region, containing about 28 genes. One of genes in the region, GTF2I, has been implicated in the hypersociability and visuospatial deficits of WBS based on genotype–phenotype correlation studies of patients with atypical deletions. In order to clarify the involvement of GTF2I in neurocognitive function, especially social behavior, we have developed and characterized Gtf2i-deficient mice. We found that homozygous deletion of Gtf2i causes lethality during embryonic development with neural tube closure defects and exencephaly, consistent with other reports. Gtf2i heterozygous animals show no gross changes in brain structure or development. Furthermore, heterozygous animals show no alterations in learning and memory, including spatial memory as assessed by the Morris water maze, but show alterations in the recognition of novel objects. Interestingly, they show increased social interaction with unfamiliar mice and do not show typical social habituation processes, reminiscent of the hypersociability observed in WBS patients. The mice do not appear to show increased anxiety, supporting a specific effect of Gtf2i on defined domains of the WBS phenotype. These data indicate that Gtf2i is involved in several aspects of embryonic development and the development of social neurocircuitry and that GTF2I haploinsufficiency could be a contributor to the hypersociability in WBS patients. En ligne : http://dx.doi.org/10.1002/aur.169 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=118 Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features / Joseph D. BUXBAUM in Molecular Autism, (February 2012)
[article]
Titre : Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features Type de document : Texte imprimé et/ou numérique Auteurs : Joseph D. BUXBAUM, Auteur ; Catalina BETANCUR, Auteur ; Ozlem BOZDAGI, Auteur ; Nathan P. DORR, Auteur ; Gregory A. ELDER, Auteur ; Patrick R. HOF, Auteur Année de publication : 2012 Article en page(s) : 24 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background
There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitute useful phenotypes in ASD models.
Methods
To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes. Findings We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1) Changes in brain and neuronal morphology; (2) electrophysiological changes; (3) neurological changes; and (4) higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms.
Conclusions
The results indicated that mutations in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD.En ligne : http://dx.doi.org/10.1186/2040-2392-3-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=153
in Molecular Autism > (February 2012) . - 24 p.[article] Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features [Texte imprimé et/ou numérique] / Joseph D. BUXBAUM, Auteur ; Catalina BETANCUR, Auteur ; Ozlem BOZDAGI, Auteur ; Nathan P. DORR, Auteur ; Gregory A. ELDER, Auteur ; Patrick R. HOF, Auteur . - 2012 . - 24 p.
Langues : Anglais (eng)
in Molecular Autism > (February 2012) . - 24 p.
Index. décimale : PER Périodiques Résumé : Background
There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitute useful phenotypes in ASD models.
Methods
To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes. Findings We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1) Changes in brain and neuronal morphology; (2) electrophysiological changes; (3) neurological changes; and (4) higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms.
Conclusions
The results indicated that mutations in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD.En ligne : http://dx.doi.org/10.1186/2040-2392-3-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=153