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Markus Wohr - One of the best experts on this subject based on the ideXlab platform.
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17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms
Molecular Autism, 2018Co-Authors: Federica Filice, Markus Wohr, Karl Jakob Vorckel, Emanuel Lauber, Beat SchwallerAbstract:Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV−/−, PV+/−), as well as SHANK1−/−, Shank3−/−, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels. Based on the hypothesis that PV expression might be increased by 17-β estradiol (E2), PV+/− mice were treated with E2 from postnatal days 5–15 and ASD-related behavior was tested between postnatal days 25 and 31. PV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/− mice in the direct reciprocal social interaction and the 3-chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV−/− mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV−/− mice. Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/− mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments.
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reduced efficacy of d amphetamine and 3 4 methylenedioxymethamphetamine in inducing hyperactivity in mice lacking the postsynaptic scaffolding protein SHANK1
Frontiers in Molecular Neuroscience, 2018Co-Authors: Ozge A Sungur, Tobias M Redecker, Elena Andres, Wiebke Durichen, Rainer K W Schwarting, Markus WohrAbstract:Genetic defects in the three SH3 and multiple ankyrin repeat domains (SHANK) genes (SHANK1, SHANK2, and SHANK3) are associated with multiple major neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BPD). Psychostimulant-induced hyperactivity is a commonly applied paradigm to assess behavioral phenotypes related to BPD and considered to be the gold standard for modeling mania-like elevated drive in mouse models. Therefore, the goal of our present study was to test whether SHANK1 plays a role in the behavioral effects of psychostimulants and whether this is associated with genotype-dependent neurochemical alterations. To this aim, male and female null mutant SHANK1-/- mice were treated with d-amphetamine (AMPH; 2.5 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy; 20 mg/kg), and psychostimulant-induced hyperactivity was compared to heterozygous SHANK1+/- and wildtype SHANK1+/+ littermate controls. Results show that SHANK1-/- mice display reduced psychostimulant-induced hyperactivity, although psychostimulants robustly stimulated locomotor activity in littermate controls. SHANK1 deletion effects emerged throughout development, were particularly prominent in adulthood, and seen in response to both psychostimulants, i.e. AMPH and MDMA. Specifically, while AMPH-induced hyperactivity was reduced but still detectable in SHANK1-/- mice, MDMA-induced hyperactivity was robustly blocked and completely absent in SHANK1-/- mice. Reduced efficacy of psychostimulants to stimulate hyperactivity in SHANK1-/- mice might be associated with alterations in the neurochemical architecture in prefrontal cortex, nucleus accumbens, and hypothalamus. Our observation that psychostimulant-induced hyperactivity is reduced rather than enhanced in SHANK1-/- mice clearly speaks against a behavioral phenotype with relevance for BPD. Lack of BPD-like phenotype is consistent with currently available human data linking mutations in SHANK2 and SHANK3 to BPD but not SHANK1.
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behavioral phenotypes and neurobiological mechanisms in the SHANK1 mouse model for autism spectrum disorder a translational perspective
Behavioural Brain Research, 2017Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Markus WohrAbstract:Abstract Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, characterized by early-onset deficits in social behavior and communication across multiple contexts, together with restricted, repetitive patterns of behavior, interests, or activities. ASD is among the most heritable neuropsychiatric conditions with heritability estimates higher than 80%, and while available evidence points to a complex set of genetic factors, the SHANK (also known as ProSAP) gene family has emerged as one of the most promising candidates. Several genetic Shank mouse models for ASD were generated, including SHANK1 knockout mice. Behavioral studies focusing on the SHANK1 knockout mouse model for ASD included assays for detecting ASD-relevant behavioral phenotypes in the following domains: (I) social behavior, (II) communication, and (III) repetitive and stereotyped patterns of behavior. In addition, assays for detecting behavioral phenotypes with relevance to comorbidities in ASD were performed, including but not limited to (IV) cognitive functioning. Here, we summarize and discuss behavioral and neuronal findings obtained in the SHANK1 knockout mouse model for ASD. We identify open research questions by comparing such findings with the symptoms present in humans diagnosed with ASD and carrying SHANK1 deletions. We conclude by discussing the implications of the behavioral and neuronal phenotypes displayed by the SHANK1 knockout mouse model for the development of future pharmacological interventions in ASD.
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aberrant cognitive phenotypes and altered hippocampal bdnf expression related to epigenetic modifications in mice lacking the post synaptic scaffolding protein SHANK1 implications for autism spectrum disorder
Hippocampus, 2017Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Magdalena C E Jochner, Hani Harb, Ayse Kilic, Holger Garn, Markus WohrAbstract:Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in SHANK1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, SHANK1-/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of SHANK1-/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in SHANK1-/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that SHANK1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target. This article is protected by copyright. All rights reserved.
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Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post‐synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder
Hippocampus, 2017Co-Authors: A. Özge Sungur, Rainer K W Schwarting, Magdalena C E Jochner, Hani Harb, Ayse Kilic, Holger Garn, Markus WohrAbstract:Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in SHANK1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, SHANK1-/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of SHANK1-/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in SHANK1-/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that SHANK1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target. This article is protected by copyright. All rights reserved.
Hansjurgen Kreienkamp - One of the best experts on this subject based on the ideXlab platform.
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a non canonical initiation site is required for efficient translation of the dendritically localized SHANK1 mrna
PLOS ONE, 2014Co-Authors: Katrin Studtmann, Jurgen Bockmann, Dietmar Richter, Stefan Kindler, Carlo Sala, Janin Olschlagerschutt, Friedrich Buck, Hansjurgen KreienkampAbstract:Local protein synthesis in dendrites enables neurons to selectively change the protein complement of individual postsynaptic sites. Though it is generally assumed that this mechanism requires tight translational control of dendritically transported mRNAs, it is unclear how translation of dendritic mRNAs is regulated. We have analyzed here translational control elements of the dendritically localized mRNA coding for the postsynaptic scaffold protein SHANK1. In its 5′ region, the human SHANK1 mRNA exhibits two alternative translation initiation sites (AUG+1 and AUG+214), three canonical upstream open reading frames (uORFs1-3) and a high GC content. In reporter assays, fragments of the 5′UTR with high GC content inhibit translation, suggesting a contribution of secondary structures. uORF3 is most relevant to translation control as it overlaps with the first in frame start codon (AUG+1), directing translation initiation to the second in frame start codon (AUG+214). Surprisingly, our analysis points to an additional uORF initiated at a non-canonical ACG start codon. Mutation of this start site leads to an almost complete loss of translation initiation at AUG+1, demonstrating that this unconventional uORF is required for SHANK1 synthesis. Our data identify a novel mechanism whereby initiation at a non-canonical site allows for translation of the main SHANK1 ORF despite a highly structured 5′UTR.
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Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities.
Journal of Biological Chemistry, 2009Co-Authors: Janin Schutt, Dietmar Richter, Hansjurgen Kreienkamp, Katrin Falley, Stefan KindlerAbstract:Abstract Functional absence of fragile X mental retardation protein (FMRP) causes the fragile X syndrome, a hereditary form of mental retardation characterized by a change in dendritic spine morphology. The RNA-binding protein FMRP has been implicated in regulating postsynaptic protein synthesis. Here we have analyzed whether the abundance of scaffold proteins and neurotransmitter receptor subunits in postsynaptic densities (PSDs) is altered in the neocortex and hippocampus of FMRP-deficient mice. Whereas the levels of several PSD components are unchanged, concentrations of SHANK1 and SAPAP scaffold proteins and various glutamate receptor subunits are altered in both adult and juvenile knock-out mice. With the exception of slightly increased hippocampal SAPAP2 mRNA levels in adult animals, altered postsynaptic protein concentrations do not correlate with similar changes in total and synaptic levels of corresponding mRNAs. Thus, loss of FMRP in neurons appears to mainly affect the translation and not the abundance of particular brain transcripts. Semi-quantitative analysis of RNA levels in FMRP immunoprecipitates showed that in the mouse brain mRNAs encoding PSD components, such as SHANK1, SAPAP1–3, PSD-95, and the glutamate receptor subunits NR1 and NR2B, are associated with FMRP. Luciferase reporter assays performed in primary cortical neurons from knock-out and wild-type mice indicate that FMRP silences translation of SHANK1 mRNAs via their 3′-untranslated region. Activation of metabotropic glutamate receptors relieves translational suppression. As SHANK1 controls dendritic spine morphology, our data suggest that dysregulation of SHANK1 synthesis may significantly contribute to the abnormal spine development and function observed in brains of fragile X syndrome patients.
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SHANK1 mrna dendritic transport by kinesin and translational control by the 5 untranslated region
Traffic, 2009Co-Authors: Katrin Falley, Peter Iglauer, Dietmar Richter, Stefan Kindler, Janin Schutt, Katharina Menke, Christoph Maas, Matthias Kneussel, Fred S Wouters, Hansjurgen KreienkampAbstract:Dendritic mRNA transport coupled with local regulation of translation enables neurons to selectively alter the protein composition of individual postsynaptic sites. We have analyzed dendritic localization of SHANK1 mRNAs; shank proteins (SHANK1–3) are scaffolding molecules of the postsynaptic density (PSD) of excitatory synapses, which are crucial for PSD assembly and the formation of dendritic spines. Live cell imaging demonstrates saltatory movements of SHANK1 mRNA containing granules along microtubules in both anterograde and retrograde directions. A population of brain messenger ribonucleoprotein particles (mRNPs) containing SHANK1 mRNAs associates with the cargo-binding domain of the motor protein KIF5C. Through expression of dominant negative proteins, we show that dendritic targeting of SHANK1 mRNA granules involves KIF5C and the KIF5-associated RNA-binding protein staufen1. While transport of SHANK1 mRNAs follows principles previously outlined for other dendritic transcripts, SHANK1 mRNAs are distinguished by their translational regulation. Translation is strongly inhibited by a GC-rich 5′untranslated region; in addition, internal ribosomal entry sites previously detected in other dendritic transcripts are absent in the SHANK1 mRNA. A concept emerges from our data in which dendritic transport of different mRNAs occurs collectively via a staufen1- and KIF5-dependent pathway, whereas their local translation is controlled individually by unique cis-acting elements.
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Postsynaptic Shank Antagonizes Dendrite Branching Induced by the Leucine-Rich Repeat Protein Densin-180
The Journal of Neuroscience, 2005Co-Authors: Arne Quitsch, Dietmar Richter, Kerstin Berhörster, Chong Wee Liew, Hansjurgen KreienkampAbstract:Leucine-rich repeat and PDZ [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] domain proteins such as scribble and Densin-180 have been implicated in the establishment of cell-cell contacts. Here, we show that Densin-180, which has been identified as a constituent of the postsynaptic density in excitatory synapses interacts with the postsynaptic scaffold protein shank (SHANK1-3). The interaction involves a two-point attachment of the C-terminal region of Densin-180 with the Src homology 3 domain and the N-terminal part of the proline-rich region of shank proteins. The N-terminal leucine-rich repeat region, which is not involved in binding shank, targets Densin-180 to the plasma membrane in transfected cells and to the basolateral membrane of epithelial cells. Nevertheless, coexpression of shank leads to a redirection of Densin-180 into intracellular clusters. In cultured hippocampal neurons, Densin-180 overexpression induces excessive branching of neuronal dendrites, which occurs at the expense of clusters for the postsynaptic marker PSD-95. Coexpression of shank3 abrogates branch formation and targets Densin-180 into postsynaptic clusters instead. Shank blocks binding of δ-catenin but not αCaM kinase II to Densin-180; because δ-catenin has been shown to induce branching and neurite formation, our data suggest a mechanism where shank could block the activation of a Densin-180-dependent signaling pathway by δ-catenin.
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Insulin receptor substrate of 53 kDa links postsynaptic shank to PSD‐95
Journal of Neurochemistry, 2004Co-Authors: Michaela Soltau, Dietmar Richter, Stefan Kindler, Kerstin Berhörster, Fritz Buck, Hansjurgen KreienkampAbstract:The insulin receptor substrate of 53 kDa (IRSp53) is a target of the small GTPase cdc42 which is strongly enriched in the postsynaptic density of excitatory synapses. IRSp53 interacts with the postsynaptic SHANK1 scaffolding molecule in a cdc42 regulated manner. The functional significance of the cdc42/IRSp53 pathway in postsynaptic sites is however, unclear. Here we identify PSD-95 as a second synaptic interaction partner of IRSp53. Interaction is mediated by a C-terminal PDZ binding motif in IRSp53 and the second PDZ domain of PSD-95. In HEK cells, overexpressed IRSp53 induces filopodia and targets PSD-95 into these processes. Immunoprecipitation and immunocytochemistry experiments demonstrate that the interaction occurs at postsynaptic sites in the brain. By virtue of its PDZ-binding and SH3 domains, IRSp53 is capable of inducing the formation of a triple complex (SHANK1/IRSp53/PSD-95).
Ozge A Sungur - One of the best experts on this subject based on the ideXlab platform.
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reduced efficacy of d amphetamine and 3 4 methylenedioxymethamphetamine in inducing hyperactivity in mice lacking the postsynaptic scaffolding protein SHANK1
Frontiers in Molecular Neuroscience, 2018Co-Authors: Ozge A Sungur, Tobias M Redecker, Elena Andres, Wiebke Durichen, Rainer K W Schwarting, Markus WohrAbstract:Genetic defects in the three SH3 and multiple ankyrin repeat domains (SHANK) genes (SHANK1, SHANK2, and SHANK3) are associated with multiple major neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BPD). Psychostimulant-induced hyperactivity is a commonly applied paradigm to assess behavioral phenotypes related to BPD and considered to be the gold standard for modeling mania-like elevated drive in mouse models. Therefore, the goal of our present study was to test whether SHANK1 plays a role in the behavioral effects of psychostimulants and whether this is associated with genotype-dependent neurochemical alterations. To this aim, male and female null mutant SHANK1-/- mice were treated with d-amphetamine (AMPH; 2.5 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy; 20 mg/kg), and psychostimulant-induced hyperactivity was compared to heterozygous SHANK1+/- and wildtype SHANK1+/+ littermate controls. Results show that SHANK1-/- mice display reduced psychostimulant-induced hyperactivity, although psychostimulants robustly stimulated locomotor activity in littermate controls. SHANK1 deletion effects emerged throughout development, were particularly prominent in adulthood, and seen in response to both psychostimulants, i.e. AMPH and MDMA. Specifically, while AMPH-induced hyperactivity was reduced but still detectable in SHANK1-/- mice, MDMA-induced hyperactivity was robustly blocked and completely absent in SHANK1-/- mice. Reduced efficacy of psychostimulants to stimulate hyperactivity in SHANK1-/- mice might be associated with alterations in the neurochemical architecture in prefrontal cortex, nucleus accumbens, and hypothalamus. Our observation that psychostimulant-induced hyperactivity is reduced rather than enhanced in SHANK1-/- mice clearly speaks against a behavioral phenotype with relevance for BPD. Lack of BPD-like phenotype is consistent with currently available human data linking mutations in SHANK2 and SHANK3 to BPD but not SHANK1.
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behavioral phenotypes and neurobiological mechanisms in the SHANK1 mouse model for autism spectrum disorder a translational perspective
Behavioural Brain Research, 2017Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Markus WohrAbstract:Abstract Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, characterized by early-onset deficits in social behavior and communication across multiple contexts, together with restricted, repetitive patterns of behavior, interests, or activities. ASD is among the most heritable neuropsychiatric conditions with heritability estimates higher than 80%, and while available evidence points to a complex set of genetic factors, the SHANK (also known as ProSAP) gene family has emerged as one of the most promising candidates. Several genetic Shank mouse models for ASD were generated, including SHANK1 knockout mice. Behavioral studies focusing on the SHANK1 knockout mouse model for ASD included assays for detecting ASD-relevant behavioral phenotypes in the following domains: (I) social behavior, (II) communication, and (III) repetitive and stereotyped patterns of behavior. In addition, assays for detecting behavioral phenotypes with relevance to comorbidities in ASD were performed, including but not limited to (IV) cognitive functioning. Here, we summarize and discuss behavioral and neuronal findings obtained in the SHANK1 knockout mouse model for ASD. We identify open research questions by comparing such findings with the symptoms present in humans diagnosed with ASD and carrying SHANK1 deletions. We conclude by discussing the implications of the behavioral and neuronal phenotypes displayed by the SHANK1 knockout mouse model for the development of future pharmacological interventions in ASD.
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aberrant cognitive phenotypes and altered hippocampal bdnf expression related to epigenetic modifications in mice lacking the post synaptic scaffolding protein SHANK1 implications for autism spectrum disorder
Hippocampus, 2017Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Magdalena C E Jochner, Hani Harb, Ayse Kilic, Holger Garn, Markus WohrAbstract:Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in SHANK1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, SHANK1-/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of SHANK1-/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in SHANK1-/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that SHANK1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target. This article is protected by copyright. All rights reserved.
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early communication deficits in the SHANK1 knockout mouse model for autism spectrum disorder developmental aspects and effects of social context
Autism Research, 2016Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Markus WohrAbstract:: Alterations in SHANK genes were repeatedly reported in autism spectrum disorder (ASD). ASD is a group of neurodevelopmental disorders diagnosed by persistent deficits in social communication/interaction across multiple contexts, with restricted/repetitive patterns of behavior. To date, diagnostic criteria for ASD are purely behaviorally defined and reliable biomarkers have still not been identified. The validity of mouse models for ASD therefore strongly relies on their behavioral phenotype. Here, we studied communication by means of isolation-induced pup ultrasonic vocalizations (USV) in the SHANK1 mouse model for ASD by comparing SHANK1(-/-) null mutant, SHANK1(+/-) heterozygous, and SHANK1(+/+) wildtype littermate controls. The first aim of the present study was to evaluate the effects of SHANK1 deletions on developmental aspects of communication in order to see whether ASD-related communication deficits are due to general impairment or delay in development. Second, we focused on social context effects on USV production. We show that SHANK1(-/-) pups vocalized less and displayed a delay in the typical inverted U-shaped developmental USV emission pattern with USV rates peaking on postnatal day (PND) 9, resulting in a prominent genotype difference on PND6. Moreover, testing under social conditions revealed even more prominently genotype-dependent deficits regardless of the familiarity of the social context. As communication by definition serves a social function, introducing a social component to the typically nonsocial test environment could therefore help to reveal communication deficits in mouse models for ASD. Together, these results indicate that SHANK1 is involved in acoustic communication across species, with genetic alterations in SHANK1 resulting in social communication/interaction deficits. Autism Res 2016, 9: 696-709. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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repetitive behaviors in the SHANK1 knockout mouse model for autism spectrum disorder developmental aspects and effects of social context
Journal of Neuroscience Methods, 2014Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Karl Jakob Vorckel, Markus WohrAbstract:Abstract Background Autism spectrum disorder (ASD) is characterized by persistent deficits in social behavior and communication, together with restricted and repetitive patterns of behavior. Several ASD candidate genes have been identified, including the SHANK gene family with its three family members SHANK1, SHANK2, and SHANK3. Methods Typically, repetitive behavior in mouse models for ASD is assessed by measuring self-grooming behavior. The first aim of the current study was to assess repetitive behaviors in SHANK1−/− null mutant, SHANK1+/− heterozygous, and SHANK1+/+ wildtype littermate control mice by means of a comprehensive approach, including the assessment of self-grooming, digging behavior, and marble burying. The second aim was to establish a test paradigm that allows for assessing the effects of social context on the occurrence of repetitive behaviors in a genotype-dependent manner. To this aim, repetitive behaviors were repeatedly tested on three consecutive days in distinct social contexts, namely in presence or absence of social odors. Results SHANK1+/− heterozygous and to a lesser extent SHANK1−/− null mutant mice displayed slightly elevated levels of self-grooming behavior as adults, but not as juveniles, with genotype differences being most prominent in the social context. In contrast to elevated self-grooming behavior, marble burying was strongly reduced in adult SHANK1+/− heterozygous and SHANK1−/− null mutant mice across social contexts, as compared to adult SHANK1+/+ wildtype littermate controls. Conclusion The opposite effects of the SHANK1 deletion on the two types of repetitive behaviors are in line with a number of studies on repetitive behaviors in other genetic Shank models.
Tobias M Bockers - One of the best experts on this subject based on the ideXlab platform.
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Secretory granules of hypophyseal and pancreatic endocrine cells contain proteins of the neuronal postsynaptic density
Cell and Tissue Research, 2007Co-Authors: Peter Redecker, Jurgen Bockmann, Tobias M BockersAbstract:The PDZ domain-containing protein Shank is a master scaffolding protein of the neuronal postsynaptic density and directly or indirectly links neurotransmitter receptors and cell adhesion molecules to the actin-based cytoskeleton. ProSAP/Shank proteins have recently also been detected in several non-neuronal cells in which they are mostly concentrated in the apical subplasmalemmal cytoplasm. In contrast, we have previously reported a more widespread cytoplasmic immunostaining pattern for the ProSAP1/Shank2 protein in endocrine cells at the light-microscopic level. Therefore, in the present study, we have determined the ultrastructural localization of ProSAP1/Shank2 and the ProSAP/Shank-interacting proteins ProSAPiP1 and IRSp53 in pancreatic islet and adenohypophyseal cells by using immunogold staining techniques. Dense immunolabeling of secretory granules including the granule core in cells such as hypophyseal somatotrophs and pancreatic B-cells indicates the unexpected presence of ProSAP/Shank and ProSAP/Shank-interacting proteins in the hormone-storing compartment of endocrine cells. Thus, ProSAP/Shank and certain ProSAP/Shank-interacting proteins exhibit distinct subcellular localizations in the different cell types, raising the possibility that the function of ProSAP/Shank proteins is more diverse than has been envisaged to date.
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Expression of postsynaptic density proteins of the ProSAP/Shank family in the thymus
Histochemistry and Cell Biology, 2006Co-Authors: Peter Redecker, Jurgen Bockmann, Tobias M BockersAbstract:PSD95-DLG-ZO1 domain-containing proteins of the ProSAP/Shank family are major scaffolding proteins of the neuronal postsynaptic density which play a pivotal role in the linkage of membrane receptors to downstream signal effectors and the actin-based cytoskeleton. Recently, ProSAP1/Shank2 has also been localized in various non-neuronal cells where it may fulfill similar functions as in neurons. We now complement these data by the study of ProSAP/Shank expression at the mRNA and protein level in a primary lymphoid organ, i.e., the thymus. Transcripts for ProSAP1/Shank2, the spliceoform Shank2E, and ProSAP2/Shank3 could be clearly detected in the thymus. Western blot and immunocytochemical analyses verified the presence of ProSAP1/Shank2 and ProSAP2/Shank3 proteins in thymic tissue. Immunoreactivity was concentrated in the whole peripheral cytoplasm of thymocytes underneath the plasma membrane. Discrete subplasmalemmal areas of pronounced ProSAP/Shank immunoreactivity could be demonstrated inside several thymocytes by confocal laser scanning microscopy. Our results establish ProSAP/Shank as a constituent of the cell cortex of thymocytes and thus lead to the hypothesis that ProSAP/Shank proteins serve as a platform for the coordination of membrane receptor-dependent signal transduction in immune cells.
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differential expression and dendritic transcript localization of shank family members identification of a dendritic targeting element in the 3 untranslated region of SHANK1 mrna
Molecular and Cellular Neuroscience, 2004Co-Authors: Tobias M Bockers, Michael R Kreutz, Mailin Seggerjunius, Peter Iglauer, Jurgen Bockmann, Eckart D Gundelfinger, Dietmar Richter, Stefan Kindler, Hansjurgen KreienkampAbstract:Abstract Shank proteins are scaffolding proteins in the postsynaptic density of excitatory synapses in the mammalian brain. In situ hybridization revealed that SHANK1/SSTRIP and Shank2/ProSAP1 mRNAs are widely expressed early in postnatal brain development whereas Shank3/ProSAP2 expression increases during postnatal development especially in the cerebellum and thalamus. SHANK1 and Shank3 (but not Shank2) mRNAs are present in the molecular layers of the hippocampus, consistent with a dendritic transcript localization. SHANK1 and Shank2 transcripts are detectable in the dendritic fields of Purkinje cells, whereas Shank3 mRNA is restricted to cerebellar granule cells. The appearance of dendritic Shank mRNAs in cerebellar Purkinje cells coincides with the onset of dendrite formation. Expression of reporter transcripts in hippocampal neurons identifies a 200-nucleotide dendritic targeting element (DTE) in the SHANK1 mRNA. The widespread presence of Shank mRNAs in dendrites suggests a role for local synthesis of Shanks in response to stimuli that induce alterations in synaptic morphology.
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Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3′ untranslated region of SHANK1 mRNA
Molecular and Cellular Neuroscience, 2004Co-Authors: Tobias M Bockers, Michael R Kreutz, Peter Iglauer, Jurgen Bockmann, Eckart D Gundelfinger, Dietmar Richter, Stefan Kindler, Mailin Segger-junius, Hansjurgen KreienkampAbstract:Abstract Shank proteins are scaffolding proteins in the postsynaptic density of excitatory synapses in the mammalian brain. In situ hybridization revealed that SHANK1/SSTRIP and Shank2/ProSAP1 mRNAs are widely expressed early in postnatal brain development whereas Shank3/ProSAP2 expression increases during postnatal development especially in the cerebellum and thalamus. SHANK1 and Shank3 (but not Shank2) mRNAs are present in the molecular layers of the hippocampus, consistent with a dendritic transcript localization. SHANK1 and Shank2 transcripts are detectable in the dendritic fields of Purkinje cells, whereas Shank3 mRNA is restricted to cerebellar granule cells. The appearance of dendritic Shank mRNAs in cerebellar Purkinje cells coincides with the onset of dendrite formation. Expression of reporter transcripts in hippocampal neurons identifies a 200-nucleotide dendritic targeting element (DTE) in the SHANK1 mRNA. The widespread presence of Shank mRNAs in dendrites suggests a role for local synthesis of Shanks in response to stimuli that induce alterations in synaptic morphology.
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Interaction of G-protein-coupled receptors with synaptic scaffolding proteins
Biochemical Society Transactions, 2002Co-Authors: Hansjurgen Kreienkamp, Dietmar Richter, Michaela Soltau, Tobias M BockersAbstract:The calcium-independent receptors for latrotoxin (CIRL1-CIRL3) constitute a family of seven-transmembrane receptors with an unsually large N-terminal extracellular domain which comprises several motifs usually found in cell adhesion molecules. By yeast two-hybrid screening, we have identified the intracellular C-termini of CIRL1 and CIRL2 as interaction partners of the PDZ domain of the proline-rich synapse-associated protein (ProSAP)/somatostatin receptor-interacting protein (SSTRIP) family of postsynaptic proteins (SSTRIP, ProSAP1 and ProSAP2, also known as SHANK1-shank3 respectively). Overlay assays indicate that the ProSAP1/shank2 PDZ domain in particular interacts strongly with the C-terminus of CIRL1 and CIRL2. Co-immuno-precipitation of ProSAP1 and CIRL1 (but not CIRL2) from rat brain extracts indicates that this interaction also occurs in vivo in rat brain. The known postsynaptic localization of ProSAP1, as well as our observation that CIRL1 (but not CIRL2) is enriched in postsynaptic density preparations from the rat brain, suggests that CIRL1 is localized pre- as well as post-synaptically in the central nervous system.
Rainer K W Schwarting - One of the best experts on this subject based on the ideXlab platform.
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reduced efficacy of d amphetamine and 3 4 methylenedioxymethamphetamine in inducing hyperactivity in mice lacking the postsynaptic scaffolding protein SHANK1
Frontiers in Molecular Neuroscience, 2018Co-Authors: Ozge A Sungur, Tobias M Redecker, Elena Andres, Wiebke Durichen, Rainer K W Schwarting, Markus WohrAbstract:Genetic defects in the three SH3 and multiple ankyrin repeat domains (SHANK) genes (SHANK1, SHANK2, and SHANK3) are associated with multiple major neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BPD). Psychostimulant-induced hyperactivity is a commonly applied paradigm to assess behavioral phenotypes related to BPD and considered to be the gold standard for modeling mania-like elevated drive in mouse models. Therefore, the goal of our present study was to test whether SHANK1 plays a role in the behavioral effects of psychostimulants and whether this is associated with genotype-dependent neurochemical alterations. To this aim, male and female null mutant SHANK1-/- mice were treated with d-amphetamine (AMPH; 2.5 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy; 20 mg/kg), and psychostimulant-induced hyperactivity was compared to heterozygous SHANK1+/- and wildtype SHANK1+/+ littermate controls. Results show that SHANK1-/- mice display reduced psychostimulant-induced hyperactivity, although psychostimulants robustly stimulated locomotor activity in littermate controls. SHANK1 deletion effects emerged throughout development, were particularly prominent in adulthood, and seen in response to both psychostimulants, i.e. AMPH and MDMA. Specifically, while AMPH-induced hyperactivity was reduced but still detectable in SHANK1-/- mice, MDMA-induced hyperactivity was robustly blocked and completely absent in SHANK1-/- mice. Reduced efficacy of psychostimulants to stimulate hyperactivity in SHANK1-/- mice might be associated with alterations in the neurochemical architecture in prefrontal cortex, nucleus accumbens, and hypothalamus. Our observation that psychostimulant-induced hyperactivity is reduced rather than enhanced in SHANK1-/- mice clearly speaks against a behavioral phenotype with relevance for BPD. Lack of BPD-like phenotype is consistent with currently available human data linking mutations in SHANK2 and SHANK3 to BPD but not SHANK1.
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behavioral phenotypes and neurobiological mechanisms in the SHANK1 mouse model for autism spectrum disorder a translational perspective
Behavioural Brain Research, 2017Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Markus WohrAbstract:Abstract Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, characterized by early-onset deficits in social behavior and communication across multiple contexts, together with restricted, repetitive patterns of behavior, interests, or activities. ASD is among the most heritable neuropsychiatric conditions with heritability estimates higher than 80%, and while available evidence points to a complex set of genetic factors, the SHANK (also known as ProSAP) gene family has emerged as one of the most promising candidates. Several genetic Shank mouse models for ASD were generated, including SHANK1 knockout mice. Behavioral studies focusing on the SHANK1 knockout mouse model for ASD included assays for detecting ASD-relevant behavioral phenotypes in the following domains: (I) social behavior, (II) communication, and (III) repetitive and stereotyped patterns of behavior. In addition, assays for detecting behavioral phenotypes with relevance to comorbidities in ASD were performed, including but not limited to (IV) cognitive functioning. Here, we summarize and discuss behavioral and neuronal findings obtained in the SHANK1 knockout mouse model for ASD. We identify open research questions by comparing such findings with the symptoms present in humans diagnosed with ASD and carrying SHANK1 deletions. We conclude by discussing the implications of the behavioral and neuronal phenotypes displayed by the SHANK1 knockout mouse model for the development of future pharmacological interventions in ASD.
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aberrant cognitive phenotypes and altered hippocampal bdnf expression related to epigenetic modifications in mice lacking the post synaptic scaffolding protein SHANK1 implications for autism spectrum disorder
Hippocampus, 2017Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Magdalena C E Jochner, Hani Harb, Ayse Kilic, Holger Garn, Markus WohrAbstract:Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in SHANK1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, SHANK1-/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of SHANK1-/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in SHANK1-/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that SHANK1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target. This article is protected by copyright. All rights reserved.
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Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post‐synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder
Hippocampus, 2017Co-Authors: A. Özge Sungur, Rainer K W Schwarting, Magdalena C E Jochner, Hani Harb, Ayse Kilic, Holger Garn, Markus WohrAbstract:Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in SHANK1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, SHANK1-/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of SHANK1-/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in SHANK1-/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that SHANK1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target. This article is protected by copyright. All rights reserved.
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early communication deficits in the SHANK1 knockout mouse model for autism spectrum disorder developmental aspects and effects of social context
Autism Research, 2016Co-Authors: Ozge A Sungur, Rainer K W Schwarting, Markus WohrAbstract:: Alterations in SHANK genes were repeatedly reported in autism spectrum disorder (ASD). ASD is a group of neurodevelopmental disorders diagnosed by persistent deficits in social communication/interaction across multiple contexts, with restricted/repetitive patterns of behavior. To date, diagnostic criteria for ASD are purely behaviorally defined and reliable biomarkers have still not been identified. The validity of mouse models for ASD therefore strongly relies on their behavioral phenotype. Here, we studied communication by means of isolation-induced pup ultrasonic vocalizations (USV) in the SHANK1 mouse model for ASD by comparing SHANK1(-/-) null mutant, SHANK1(+/-) heterozygous, and SHANK1(+/+) wildtype littermate controls. The first aim of the present study was to evaluate the effects of SHANK1 deletions on developmental aspects of communication in order to see whether ASD-related communication deficits are due to general impairment or delay in development. Second, we focused on social context effects on USV production. We show that SHANK1(-/-) pups vocalized less and displayed a delay in the typical inverted U-shaped developmental USV emission pattern with USV rates peaking on postnatal day (PND) 9, resulting in a prominent genotype difference on PND6. Moreover, testing under social conditions revealed even more prominently genotype-dependent deficits regardless of the familiarity of the social context. As communication by definition serves a social function, introducing a social component to the typically nonsocial test environment could therefore help to reveal communication deficits in mouse models for ASD. Together, these results indicate that SHANK1 is involved in acoustic communication across species, with genetic alterations in SHANK1 resulting in social communication/interaction deficits. Autism Res 2016, 9: 696-709. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.