30 recherche sur le mot-clé 'shank3'

Shank3 deficiency elicits autistic-like behaviors by activating p38? in hypothalamic AgRP neurons / Shanshan WU in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 14p. Titre : Shank3 deficiency elicits autistic-like behaviors by activating p38? in hypothalamic AgRP neurons Type de document : texte imprimé Auteurs : Shanshan WU, Auteur ; Jing WANG, Auteur ; Zicheng ZHANG, Auteur ; Xinchen JIN, Auteur ; Yang XU, Auteur ; Youwen SI, Auteur ; Yixiao LIANG, Auteur ; Yueping GE, Auteur ; Huidong ZHAN, Auteur ; Li PENG, Auteur ; Wenkai BI, Auteur ; Dandan LUO, Auteur ; Mengzhu LI, Auteur ; Bo MENG, Auteur ; Qingbo GUAN, Auteur ; Jiajun ZHAO, Auteur ; Ling GAO, Auteur ; Zhao HE, Auteur Article en page(s) : 14p. Langues : Anglais (eng) Mots-clés : Animals  Mice  Agouti-Related Protein/genetics/metabolism  Arcuate Nucleus of Hypothalamus/metabolism  Autistic Disorder/genetics/metabolism  Hypothalamus/metabolism  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics/metabolism  Neurons/metabolism  Mitogen-Activated Protein Kinase 14/metabolism  AgRP  Autism  Shank3  Sociability  Stereotypic behavior  p38? Index. décimale : PER Périodiques Résumé : BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38 , a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38 are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3(-/-)) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38 in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38 . T180A and Y182F mutations expressed inactive p38 . RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38 activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3(-/-) mice. Consistently, overexpression of p38 in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38 in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. In contrast, activated p38 in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38 in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38 signaling in AgRP neurons, suggesting that p38 signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism. En ligne : https://dx.doi.org/10.1186/s13229-024-00595-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Shank3 deficiency elicits autistic-like behaviors by activating p38? in hypothalamic AgRP neurons [texte imprimé] / Shanshan WU, Auteur ; Jing WANG, Auteur ; Zicheng ZHANG, Auteur ; Xinchen JIN, Auteur ; Yang XU, Auteur ; Youwen SI, Auteur ; Yixiao LIANG, Auteur ; Yueping GE, Auteur ; Huidong ZHAN, Auteur ; Li PENG, Auteur ; Wenkai BI, Auteur ; Dandan LUO, Auteur ; Mengzhu LI, Auteur ; Bo MENG, Auteur ; Qingbo GUAN, Auteur ; Jiajun ZHAO, Auteur ; Ling GAO, Auteur ; Zhao HE, Auteur . - 14p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 14p. Mots-clés : Animals  Mice  Agouti-Related Protein/genetics/metabolism  Arcuate Nucleus of Hypothalamus/metabolism  Autistic Disorder/genetics/metabolism  Hypothalamus/metabolism  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics/metabolism  Neurons/metabolism  Mitogen-Activated Protein Kinase 14/metabolism  AgRP  Autism  Shank3  Sociability  Stereotypic behavior  p38? Index. décimale : PER Périodiques Résumé : BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38 , a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38 are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3(-/-)) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38 in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38 . T180A and Y182F mutations expressed inactive p38 . RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38 activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3(-/-) mice. Consistently, overexpression of p38 in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38 in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. In contrast, activated p38 in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38 in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38 signaling in AgRP neurons, suggesting that p38 signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism. En ligne : https://dx.doi.org/10.1186/s13229-024-00595-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism / Thomas C. JARAMILLO in Autism Research, 9-3 (March 2016)  

Public ISBD [article]  inAutism Research > 9-3 (March 2016) . - p.350-375 Titre : Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism Type de document : texte imprimé Auteurs : Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur Article en page(s) : p.350-375 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  Shank3  Phelan-McDermid syndrome  mouse model  grooming Index. décimale : PER Périodiques Résumé : Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1529 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285 [article] Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism [texte imprimé] / Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur . - p.350-375. Langues : Anglais (eng) in Autism Research > 9-3 (March 2016) . - p.350-375 Mots-clés : autism spectrum disorder  Shank3  Phelan-McDermid syndrome  mouse model  grooming Index. décimale : PER Périodiques Résumé : Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1529 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285

Behavioral decline in Shank3(?ex4-22) mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes / James O BEAVERS ; Romana HYDE ; Roseline EWA ; Amber SCHWERTMAN ; Sarahi PORCAYO ; Ben D. RICHARDSON in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 52 Titre : Behavioral decline in Shank3(?ex4-22) mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes Type de document : texte imprimé Auteurs : James O BEAVERS, Auteur ; Romana HYDE, Auteur ; Roseline EWA, Auteur ; Amber SCHWERTMAN, Auteur ; Sarahi PORCAYO, Auteur ; Ben D. RICHARDSON, Auteur Article en page(s) : 52 Langues : Anglais (eng) Mots-clés : Animals  *Nerve Tissue Proteins/metabolism/genetics  *Mice, Knockout  *Synapses/metabolism  Male  *Behavior, Animal  Mice  *Excitatory Postsynaptic Potentials  Female  *Cerebellum/metabolism  Microfilament Proteins/metabolism/genetics  Glutamic Acid/metabolism  Exons  Mice, Inbred C57BL  Neurons/metabolism  Ampar  Autism spectrum disorder  Cerebellum  Glutamate receptor  Granule cell  Mouse behavior  Phelan-McDermid syndrome  Shank3  accordance with protocols approved by the Institutional Animal Care and Use  Committee at Southern Illinois Universe - School of Medicine or the University of  Idaho. Consent for publication: Not applicable. Competing interests: The authors  declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although Shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in Shank3(?ex4-22) mice at two developmental stages. METHODS: Shank3(?ex4-22) wildtype, heterozygous, and homozygous knockout mice lacking exons 4-22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5-7 weeks old) and adult (3-5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of Shank3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology. RESULTS: Deletion of Shank3 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult Shank3(?ex4-22) knockout male mice, while self-grooming was uniquely elevated in males across both age groups. Heterozygous mice showed little to no changes in behavioral phenotypes in most behavioral tests. Immunofluorescence staining indicated the presence of Shank3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identified a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs. LIMITATIONS: Other behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how Shank3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum and whether these changes shape the behavioral phenotype. CONCLUSIONS: Our findings reveal an age-related exacerbation of behavioral impairments in Shank3(?ex4-22) mutant mice. These results suggest that Shank3 may alter the function of glutamatergic receptors at the mossy fiber-cerebellar granule cell synapse as a potential mechanism causing cerebellar disruption in ASD. En ligne : https://dx.doi.org/10.1186/s13229-024-00628-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Behavioral decline in Shank3(?ex4-22) mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes [texte imprimé] / James O BEAVERS, Auteur ; Romana HYDE, Auteur ; Roseline EWA, Auteur ; Amber SCHWERTMAN, Auteur ; Sarahi PORCAYO, Auteur ; Ben D. RICHARDSON, Auteur . - 52. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 52 Mots-clés : Animals  *Nerve Tissue Proteins/metabolism/genetics  *Mice, Knockout  *Synapses/metabolism  Male  *Behavior, Animal  Mice  *Excitatory Postsynaptic Potentials  Female  *Cerebellum/metabolism  Microfilament Proteins/metabolism/genetics  Glutamic Acid/metabolism  Exons  Mice, Inbred C57BL  Neurons/metabolism  Ampar  Autism spectrum disorder  Cerebellum  Glutamate receptor  Granule cell  Mouse behavior  Phelan-McDermid syndrome  Shank3  accordance with protocols approved by the Institutional Animal Care and Use  Committee at Southern Illinois Universe - School of Medicine or the University of  Idaho. Consent for publication: Not applicable. Competing interests: The authors  declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although Shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in Shank3(?ex4-22) mice at two developmental stages. METHODS: Shank3(?ex4-22) wildtype, heterozygous, and homozygous knockout mice lacking exons 4-22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5-7 weeks old) and adult (3-5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of Shank3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology. RESULTS: Deletion of Shank3 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult Shank3(?ex4-22) knockout male mice, while self-grooming was uniquely elevated in males across both age groups. Heterozygous mice showed little to no changes in behavioral phenotypes in most behavioral tests. Immunofluorescence staining indicated the presence of Shank3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identified a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs. LIMITATIONS: Other behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how Shank3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum and whether these changes shape the behavioral phenotype. CONCLUSIONS: Our findings reveal an age-related exacerbation of behavioral impairments in Shank3(?ex4-22) mutant mice. These results suggest that Shank3 may alter the function of glutamatergic receptors at the mossy fiber-cerebellar granule cell synapse as a potential mechanism causing cerebellar disruption in ASD. En ligne : https://dx.doi.org/10.1186/s13229-024-00628-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications / Jan Philipp DELLING in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications Type de document : texte imprimé Auteurs : Jan Philipp DELLING, Auteur ; Tobias M. BOECKERS, Auteur Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Chromosome Deletion  Chromosome Disorders  Humans  Mice  Microfilament Proteins/genetics  Nerve Tissue Proteins/genetics/metabolism  Phenotype  Rats  asd  Autism spectrum disorder  pmds  Phelan-McDermid syndrome  shank3  Therapy Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. MAIN TEXT: This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. CONCLUSIONS: Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors. En ligne : https://dx.doi.org/10.1186/s11689-021-09397-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications [texte imprimé] / Jan Philipp DELLING, Auteur ; Tobias M. BOECKERS, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Chromosome Deletion  Chromosome Disorders  Humans  Mice  Microfilament Proteins/genetics  Nerve Tissue Proteins/genetics/metabolism  Phenotype  Rats  asd  Autism spectrum disorder  pmds  Phelan-McDermid syndrome  shank3  Therapy Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. MAIN TEXT: This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. CONCLUSIONS: Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors. En ligne : https://dx.doi.org/10.1186/s11689-021-09397-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Copy number variations of SHANK3 and related sensory profiles in Egyptian children with autism spectrum disorder / Nagwa A. MEGUID in Research in Autism Spectrum Disorders, 75 (July 2020)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 75 (July 2020) . - p.101558 Titre : Copy number variations of SHANK3 and related sensory profiles in Egyptian children with autism spectrum disorder Type de document : texte imprimé Auteurs : Nagwa A. MEGUID, Auteur ; Ola M. EID, Auteur ; Mona REDA, Auteur ; Dina Y. ELALFY, Auteur ; Fatma HUSSEIN, Auteur Article en page(s) : p.101558 Langues : Anglais (eng) Mots-clés : Autism  Copy number variations  SHANK3  Sensory profiles  MLPA Index. décimale : PER Périodiques Résumé : Background Current estimates indicate that >80 % of children with autism spectrum disorder (ASD) exhibit concomitant sensory processing problems and hyper- or hypo-reactivity to sensory input. These are now included as diagnostic criteria for ASD in the Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition. Chromosomal rearrangements, copy number variations (CNVs), and coding sequence variants involving >100 genes have been identified in patients with ASD. Studying the CNVs of one such gene, SHANK3, and the associated phenotype in patients with ASD could provide insights that will guide future ASD treatments and interventions. Objective To assess SHANK3 CNVs in children with ASD and investigate their sensory processing patterns using the Short Sensory Profile (SSP). Subjects and methods Forty children with ASD were assessed using the Autism Diagnostic Interview-Revised. SSP was used to evaluate atypical sensory behavior, e.g., hyper- or hypo-reactivity to sensory input or unusual sensory interests. SHANK3 CNVs were assessed in these children using Multiplex Ligation-dependent Probe Amplification. Results Of the 40 cases, 77.5 % showed sensory reactivity symptoms. The greatest difference from normality was observed in the under-responsive/seeks sensation domain, followed by the tactile sensitivity domain, whereas hypo-activity (low-energy/weak domain) was closest to normal. The sensory reactivity symptoms were significantly correlated with the severity of ASD. However, only three of the 40 cases had de novo duplications at 22q13.33. The duplications included SHANK3 in two of the cases and only the distal flanking region of SHANK3 in the third case. All three duplication cases also showed symptoms associated with the low-energy/weak domain. Conclusion We found that children with ASD exhibited sensory processing problems. The SHANK3 copy number gains found demonstrate the gene dosage effect of SHANK3 in ASD pathogenesis. This study adds to the growing understanding of 22q13 duplications that include SHANK3. En ligne : https://doi.org/10.1016/j.rasd.2020.101558 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=426 [article] Copy number variations of SHANK3 and related sensory profiles in Egyptian children with autism spectrum disorder [texte imprimé] / Nagwa A. MEGUID, Auteur ; Ola M. EID, Auteur ; Mona REDA, Auteur ; Dina Y. ELALFY, Auteur ; Fatma HUSSEIN, Auteur . - p.101558. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 75 (July 2020) . - p.101558 Mots-clés : Autism  Copy number variations  SHANK3  Sensory profiles  MLPA Index. décimale : PER Périodiques Résumé : Background Current estimates indicate that >80 % of children with autism spectrum disorder (ASD) exhibit concomitant sensory processing problems and hyper- or hypo-reactivity to sensory input. These are now included as diagnostic criteria for ASD in the Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition. Chromosomal rearrangements, copy number variations (CNVs), and coding sequence variants involving >100 genes have been identified in patients with ASD. Studying the CNVs of one such gene, SHANK3, and the associated phenotype in patients with ASD could provide insights that will guide future ASD treatments and interventions. Objective To assess SHANK3 CNVs in children with ASD and investigate their sensory processing patterns using the Short Sensory Profile (SSP). Subjects and methods Forty children with ASD were assessed using the Autism Diagnostic Interview-Revised. SSP was used to evaluate atypical sensory behavior, e.g., hyper- or hypo-reactivity to sensory input or unusual sensory interests. SHANK3 CNVs were assessed in these children using Multiplex Ligation-dependent Probe Amplification. Results Of the 40 cases, 77.5 % showed sensory reactivity symptoms. The greatest difference from normality was observed in the under-responsive/seeks sensation domain, followed by the tactile sensitivity domain, whereas hypo-activity (low-energy/weak domain) was closest to normal. The sensory reactivity symptoms were significantly correlated with the severity of ASD. However, only three of the 40 cases had de novo duplications at 22q13.33. The duplications included SHANK3 in two of the cases and only the distal flanking region of SHANK3 in the third case. All three duplication cases also showed symptoms associated with the low-energy/weak domain. Conclusion We found that children with ASD exhibited sensory processing problems. The SHANK3 copy number gains found demonstrate the gene dosage effect of SHANK3 in ASD pathogenesis. This study adds to the growing understanding of 22q13 duplications that include SHANK3. En ligne : https://doi.org/10.1016/j.rasd.2020.101558 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=426

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