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

Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice / Andrea Pérez ARÉVALO ; Ines GRAF ; Rong ZHANG ; Juergen BOCKMANN ; Anne-Kathrin LUTZ ; Tobias M. BOECKERS in Molecular Autism, 14 (2023)  

Public ISBD [article]  inMolecular Autism > 14 (2023) . - 1 p. Titre : Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice Type de document : texte imprimé Auteurs : Andrea Pérez ARÉVALO, Auteur ; Ines GRAF, Auteur ; Rong ZHANG, Auteur ; Juergen BOCKMANN, Auteur ; Anne-Kathrin LUTZ, Auteur ; Tobias M. BOECKERS, Auteur Article en page(s) : 1 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is mainly characterized by deficits in social interaction and communication and repetitive behaviors. Known causes of ASD are mutations of certain risk genes like the postsynaptic protein SHANK3 and environmental factors including prenatal infections. METHODS: To analyze the gene-environment interplay in ASD, we combined the Shank3 11-/-?ASD mouse model with maternal immune activation (MIA) via an intraperitoneal injection of polyinosinic/polycytidylic acid (Poly I:C) on gestational day 12.5. The offspring of the injected dams was further analyzed for autistic-like behaviors and comorbidities followed by biochemical experiments with a focus on synaptic analysis. RESULTS: We show that the two-hit mice exhibit excessive grooming and deficits in social behavior more prominently than the Shank3 11-/-?mice. Interestingly, these behavioral changes were accompanied by an unexpected upregulation of postsynaptic density (PSD) proteins at excitatory synapses in striatum, hippocampus and prefrontal cortex. LIMITATIONS: We found several PSD proteins to be increased in the two-hit mice; however, we can only speculate about possible pathways behind the worsening of the autistic phenotype in those mice. CONCLUSIONS: With this study, we demonstrate that there is an interplay between genetic susceptibility and environmental factors defining the severity of ASD symptoms. Moreover, we show that a general misbalance of PSD proteins at excitatory synapses is linked to ASD symptoms, making this two-hit model a promising tool for the investigation of the complex pathophysiology of neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1186/s13229-022-00532-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513 [article] Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice [texte imprimé] / Andrea Pérez ARÉVALO, Auteur ; Ines GRAF, Auteur ; Rong ZHANG, Auteur ; Juergen BOCKMANN, Auteur ; Anne-Kathrin LUTZ, Auteur ; Tobias M. BOECKERS, Auteur . - 1 p. Langues : Anglais (eng) in Molecular Autism > 14 (2023) . - 1 p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is mainly characterized by deficits in social interaction and communication and repetitive behaviors. Known causes of ASD are mutations of certain risk genes like the postsynaptic protein SHANK3 and environmental factors including prenatal infections. METHODS: To analyze the gene-environment interplay in ASD, we combined the Shank3 11-/-?ASD mouse model with maternal immune activation (MIA) via an intraperitoneal injection of polyinosinic/polycytidylic acid (Poly I:C) on gestational day 12.5. The offspring of the injected dams was further analyzed for autistic-like behaviors and comorbidities followed by biochemical experiments with a focus on synaptic analysis. RESULTS: We show that the two-hit mice exhibit excessive grooming and deficits in social behavior more prominently than the Shank3 11-/-?mice. Interestingly, these behavioral changes were accompanied by an unexpected upregulation of postsynaptic density (PSD) proteins at excitatory synapses in striatum, hippocampus and prefrontal cortex. LIMITATIONS: We found several PSD proteins to be increased in the two-hit mice; however, we can only speculate about possible pathways behind the worsening of the autistic phenotype in those mice. CONCLUSIONS: With this study, we demonstrate that there is an interplay between genetic susceptibility and environmental factors defining the severity of ASD symptoms. Moreover, we show that a general misbalance of PSD proteins at excitatory synapses is linked to ASD symptoms, making this two-hit model a promising tool for the investigation of the complex pathophysiology of neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1186/s13229-022-00532-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513

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

Shank1 and Prosap1/Shank2 Mouse Models of Autism / Michael J. SCHMEISSER in Autism - Open Access, 2-4 (December 2012)  

Public ISBD [article]  inAutism - Open Access > 2-4 (December 2012) . - 4 p. Titre : Shank1 and Prosap1/Shank2 Mouse Models of Autism Type de document : texte imprimé Auteurs : Michael J. SCHMEISSER, Auteur ; Tobias M. BOECKERS, Auteur Année de publication : 2012 Article en page(s) : 4 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Over the last decade, mutations of genes coding for synaptic proteins including postsynaptic ProSAP/Shank scaffolds, were found to play a central role in autism pathogenesis. Strikingly, alterations within the human genes of all three ProSAP/Shank family members called SHANK1, PROSAP1/SHANK2 and PROSAP2/SHANK3 have been detected in patients with Autism Spectrum Disorders (ASDs). Due to the fact, that the patho-mechanisms caused by those genetic alterations are still far from being understood and that the development of therapeutic options crucially relies on the latter understanding, the generation and thorough analysis of animal models is an essential step. Here, we review existing mouse models of Shank1 and ProSAP1/Shank2 disruption with respect to neurobiological, neurophysiological and neurobehavioral phenotypes and give some future directions towards the conception of therapeutic strategies. En ligne : http://dx.doi.org/10.4172/2165-7890.1000106 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=211 [article] Shank1 and Prosap1/Shank2 Mouse Models of Autism [texte imprimé] / Michael J. SCHMEISSER, Auteur ; Tobias M. BOECKERS, Auteur . - 2012 . - 4 p. Langues : Anglais (eng) in Autism - Open Access > 2-4 (December 2012) . - 4 p. Index. décimale : PER Périodiques Résumé : Over the last decade, mutations of genes coding for synaptic proteins including postsynaptic ProSAP/Shank scaffolds, were found to play a central role in autism pathogenesis. Strikingly, alterations within the human genes of all three ProSAP/Shank family members called SHANK1, PROSAP1/SHANK2 and PROSAP2/SHANK3 have been detected in patients with Autism Spectrum Disorders (ASDs). Due to the fact, that the patho-mechanisms caused by those genetic alterations are still far from being understood and that the development of therapeutic options crucially relies on the latter understanding, the generation and thorough analysis of animal models is an essential step. Here, we review existing mouse models of Shank1 and ProSAP1/Shank2 disruption with respect to neurobiological, neurophysiological and neurobehavioral phenotypes and give some future directions towards the conception of therapeutic strategies. En ligne : http://dx.doi.org/10.4172/2165-7890.1000106 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=211

Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model / Najwa OUALI ALAMI ; Oumayma AOUSJI ; Esther POGATZKI-ZAHN ; Peter K. ZAHN ; Hanna WILHELM ; Dhruva DESHPANDE ; Elmira KHATAMSAZ ; Alberto CATANESE ; Sarah WOELFLE ; Michael SCHÖN ; Sanjay JAIN ; Stefanie GRABRUCKER ; Albert C. LUDOLPH ; Chiara VERPELLI ; Jens MICHAELIS ; Tobias M. BOECKERS ; Francesco ROSELLI in Molecular Autism, 14 (2023)  

Public ISBD [article]  inMolecular Autism > 14 (2023) . - 21 p. Titre : Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model Type de document : texte imprimé Auteurs : Najwa OUALI ALAMI, Auteur ; Oumayma AOUSJI, Auteur ; Esther POGATZKI-ZAHN, Auteur ; Peter K. ZAHN, Auteur ; Hanna WILHELM, Auteur ; Dhruva DESHPANDE, Auteur ; Elmira KHATAMSAZ, Auteur ; Alberto CATANESE, Auteur ; Sarah WOELFLE, Auteur ; Michael SCHÖN, Auteur ; Sanjay JAIN, Auteur ; Stefanie GRABRUCKER, Auteur ; Albert C. LUDOLPH, Auteur ; Chiara VERPELLI, Auteur ; Jens MICHAELIS, Auteur ; Tobias M. BOECKERS, Auteur ; Francesco ROSELLI, Auteur Article en page(s) : 21 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. METHODS: We have used a Shank2(-/-) mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. RESULTS: We determined that Shank2(-/-) mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2(-/-) mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2(-/-) mice. LIMITATIONS: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. CONCLUSION: Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD. En ligne : http://dx.doi.org/10.1186/s13229-023-00552-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513 [article] Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model [texte imprimé] / Najwa OUALI ALAMI, Auteur ; Oumayma AOUSJI, Auteur ; Esther POGATZKI-ZAHN, Auteur ; Peter K. ZAHN, Auteur ; Hanna WILHELM, Auteur ; Dhruva DESHPANDE, Auteur ; Elmira KHATAMSAZ, Auteur ; Alberto CATANESE, Auteur ; Sarah WOELFLE, Auteur ; Michael SCHÖN, Auteur ; Sanjay JAIN, Auteur ; Stefanie GRABRUCKER, Auteur ; Albert C. LUDOLPH, Auteur ; Chiara VERPELLI, Auteur ; Jens MICHAELIS, Auteur ; Tobias M. BOECKERS, Auteur ; Francesco ROSELLI, Auteur . - 21 p. Langues : Anglais (eng) in Molecular Autism > 14 (2023) . - 21 p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. METHODS: We have used a Shank2(-/-) mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. RESULTS: We determined that Shank2(-/-) mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2(-/-) mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2(-/-) mice. LIMITATIONS: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. CONCLUSION: Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD. En ligne : http://dx.doi.org/10.1186/s13229-023-00552-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513

Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling / Silvia LANDI ; Alessia STEFANONI ; Gabriele NARDI ; Marica ALBANESI ; Helen F. BAUER ; Enrico PRACUCCI ; Michael SCHÖN ; Gian Michele RATTO ; Tobias M. BOECKERS ; Carlo SALA ; Chiara VERPELLI in Molecular Autism, 14 (2023)  

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