Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions / Takeshi SAKURAI in Autism Research, 4-1 (February 2011)  

Public ISBD [article]  inAutism Research > 4-1 (February 2011) . - p.28-39 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 [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

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)  

Public ISBD [article]  inMolecular Autism > (December 2010) . - 47 p. Titre : Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication Type de document : Texte imprimé et/ou numérique Auteurs : Ozlem BOZDAGI, Auteur ; Takeshi SAKURAI, Auteur ; Danae PAPAPETROU, Auteur ; Xiaobin WANG, Auteur ; Dara L. DICKSTEIN, Auteur ; Nagahide TAKAHASHI, Auteur ; Yuji KAJIWARA, Auteur ; Mu YANG, Auteur ; Adam M. KATZ, Auteur ; Maria Luisa SCATTONI, Auteur ; Mark J. HARRIS, Auteur ; Roheeni SAXENA, Auteur ; Jill L. SILVERMAN, Auteur ; Jacqueline N. CRAWLEY, Auteur ; Qiang ZHOU, Auteur ; Patrick R. HOF, Auteur ; Joseph D. BUXBAUM, Auteur Année de publication : 2010 Article en page(s) : 47 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. Methods We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. Results In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with theta-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. Conclusions We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes. En ligne : http://dx.doi.org/10.1186/2040-2392-1-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=114 [article] Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication [Texte imprimé et/ou numérique] / Ozlem BOZDAGI, Auteur ; Takeshi SAKURAI, Auteur ; Danae PAPAPETROU, Auteur ; Xiaobin WANG, Auteur ; Dara L. DICKSTEIN, Auteur ; Nagahide TAKAHASHI, Auteur ; Yuji KAJIWARA, Auteur ; Mu YANG, Auteur ; Adam M. KATZ, Auteur ; Maria Luisa SCATTONI, Auteur ; Mark J. HARRIS, Auteur ; Roheeni SAXENA, Auteur ; Jill L. SILVERMAN, Auteur ; Jacqueline N. CRAWLEY, Auteur ; Qiang ZHOU, Auteur ; Patrick R. HOF, Auteur ; Joseph D. BUXBAUM, Auteur . - 2010 . - 47 p. Langues : Anglais (eng) in Molecular Autism > (December 2010) . - 47 p. Index. décimale : PER Périodiques Résumé : SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. Methods We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. Results In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with theta-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. Conclusions We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes. En ligne : http://dx.doi.org/10.1186/2040-2392-1-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=114

A large-scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders / Takeshi SAKURAI in Autism Research, 1-4 (August 2008)  

Public ISBD [article]  inAutism Research > 1-4 (August 2008) . - p.251-257 Titre : A large-scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Takeshi SAKURAI, Auteur ; Jennifer REICHERT, Auteur ; Joseph D. BUXBAUM, Auteur ; Ellen J. HOFFMAN, Auteur ; Guiqing CAI, Auteur ; Hywel B. JONES, Auteur ; Malek FAHAM, Auteur Année de publication : 2008 Article en page(s) : p.251-257 Langues : Anglais (eng) Mots-clés : resequencing rare-variants serotonin rigid-compulsive-behavior Index. décimale : PER Périodiques Résumé : In the current study we explored the hypothesis that rare variants in SLC6A4 contribute to autism susceptibility and to rigid-compulsive behaviors in autism. We made use of a large number of unrelated cases with autism spectrum disorders (350) and controls (420) and screened for rare exonic variants in SLC6A4 by a high-throughput method followed by sequencing. We observed no difference in the frequency of such variants in the two groups, irrespective of how we defined the rare variants. Furthermore, we did not observe an association of rare coding variants in SLC6A4 with rigid-compulsive traits scores in the cases. These results do not support a significant role for rare coding variants in SLC6A4 in autism spectrum disorders, nor do they support a significant role for SLC6A4 in rigid-compulsive traits in these disorders. En ligne : http://dx.doi.org/10.1002/aur.30 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=932 [article] A large-scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders [Texte imprimé et/ou numérique] / Takeshi SAKURAI, Auteur ; Jennifer REICHERT, Auteur ; Joseph D. BUXBAUM, Auteur ; Ellen J. HOFFMAN, Auteur ; Guiqing CAI, Auteur ; Hywel B. JONES, Auteur ; Malek FAHAM, Auteur . - 2008 . - p.251-257. Langues : Anglais (eng) in Autism Research > 1-4 (August 2008) . - p.251-257 Mots-clés : resequencing rare-variants serotonin rigid-compulsive-behavior Index. décimale : PER Périodiques Résumé : In the current study we explored the hypothesis that rare variants in SLC6A4 contribute to autism susceptibility and to rigid-compulsive behaviors in autism. We made use of a large number of unrelated cases with autism spectrum disorders (350) and controls (420) and screened for rare exonic variants in SLC6A4 by a high-throughput method followed by sequencing. We observed no difference in the frequency of such variants in the two groups, irrespective of how we defined the rare variants. Furthermore, we did not observe an association of rare coding variants in SLC6A4 with rigid-compulsive traits scores in the cases. These results do not support a significant role for rare coding variants in SLC6A4 in autism spectrum disorders, nor do they support a significant role for SLC6A4 in rigid-compulsive traits in these disorders. En ligne : http://dx.doi.org/10.1002/aur.30 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=932

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