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 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] / 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

Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism / David M. JAMES in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 3 p. Titre : Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism Type de document : texte imprimé Auteurs : David M. JAMES, Auteur ; Robert A. KOZOL, Auteur ; Yuji KAJIWARA, Auteur ; Adam L. WAHL, Auteur ; Emily C. STORRS, Auteur ; Joseph D. BUXBAUM, Auteur ; Mason KLEIN, Auteur ; Baharak MOSHIREE, Auteur ; Julia E. DALLMAN, Auteur Article en page(s) : 3 p. Langues : Anglais (eng) Mots-clés : *Digestive transit  *Enteroendocrine  *Peristaltic rate  *Phelan-McDermid syndrome  approved by the Institutional Animal Care and Use Committee of University of  Miami.The authors declare that they have no competing interests.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background and aims: Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods: To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abDeltaC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abDeltaC (+/-) heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results: Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abDeltaC (+/-) mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abDeltaC (+/-) mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abDeltaC (+/-) and shank3abDeltaC (-/-) mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abDeltaC (+/-) larvae. Conclusions: Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0250-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism [texte imprimé] / David M. JAMES, Auteur ; Robert A. KOZOL, Auteur ; Yuji KAJIWARA, Auteur ; Adam L. WAHL, Auteur ; Emily C. STORRS, Auteur ; Joseph D. BUXBAUM, Auteur ; Mason KLEIN, Auteur ; Baharak MOSHIREE, Auteur ; Julia E. DALLMAN, Auteur . - 3 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 3 p. Mots-clés : *Digestive transit  *Enteroendocrine  *Peristaltic rate  *Phelan-McDermid syndrome  approved by the Institutional Animal Care and Use Committee of University of  Miami.The authors declare that they have no competing interests.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background and aims: Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods: To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abDeltaC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abDeltaC (+/-) heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results: Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abDeltaC (+/-) mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abDeltaC (+/-) mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abDeltaC (+/-) and shank3abDeltaC (-/-) mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abDeltaC (+/-) larvae. Conclusions: Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0250-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID / Daniela M. COCHOY in Molecular Autism, (April 2015)  

Public ISBD [article]  inMolecular Autism > (April 2015) . - p.1-13 Titre : Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID Type de document : texte imprimé Auteurs : Daniela M. COCHOY, Auteur ; Alexander KOLEVZON, Auteur ; Yuji KAJIWARA, Auteur ; Michael SCHOEN, Auteur ; Maria PASCUAL-LUCAS, Auteur ; Stacey LURIE, Auteur ; Joseph D. BUXBAUM, Auteur ; Tobias M. BOECKERS, Auteur ; Michael J. SCHMEISSER, Auteur Année de publication : 2015 Article en page(s) : p.1-13 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : SHANK proteins are crucial for the formation and plasticity of excitatory synapses. Although mutations in all three SHANK genes are associated with autism spectrum disorder (ASD), SHANK3 appears to be the major ASD gene with a prevalence of approximately 0.5% for SHANK3 mutations in ASD, with higher rates in individuals with ASD and intellectual disability (ID). Interestingly, the most relevant mutations are typically de novo and often are frameshift or nonsense mutations resulting in a premature stop and a truncation of SHANK3 protein. En ligne : http://dx.doi.org/10.1186/s13229-015-0020-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID [texte imprimé] / Daniela M. COCHOY, Auteur ; Alexander KOLEVZON, Auteur ; Yuji KAJIWARA, Auteur ; Michael SCHOEN, Auteur ; Maria PASCUAL-LUCAS, Auteur ; Stacey LURIE, Auteur ; Joseph D. BUXBAUM, Auteur ; Tobias M. BOECKERS, Auteur ; Michael J. SCHMEISSER, Auteur . - 2015 . - p.1-13. Langues : Anglais (eng) in Molecular Autism > (April 2015) . - p.1-13 Index. décimale : PER Périodiques Résumé : SHANK proteins are crucial for the formation and plasticity of excitatory synapses. Although mutations in all three SHANK genes are associated with autism spectrum disorder (ASD), SHANK3 appears to be the major ASD gene with a prevalence of approximately 0.5% for SHANK3 mutations in ASD, with higher rates in individuals with ASD and intellectual disability (ID). Interestingly, the most relevant mutations are typically de novo and often are frameshift or nonsense mutations resulting in a premature stop and a truncation of SHANK3 protein. En ligne : http://dx.doi.org/10.1186/s13229-015-0020-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

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