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Markus Wohr - 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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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, Karl Jakob Vorckel, Rainer K W Schwarting, 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.
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Communication Impairments in Mice Lacking Shank1: Reduced Levels of Ultrasonic Vocalizations and Scent Marking Behavior
2013Co-Authors: Markus Wohr, Florence I Roullet, Albert Y Hung, Morgan Sheng, Jacqueline N CrawleyAbstract:Autism is a neurodevelopmental disorder with a strong genetic component. Core symptoms are abnormal reciprocal social interactions, qualitative impairments in communication, and repetitive and stereotyped patterns of behavior with restricted interests. Candidate genes for autism include the SHANK gene family, as mutations in SHANK2 and SHANK3 have been detected in several autistic individuals. SHANK genes code for a family of scaffolding proteins located in the postsynaptic density of excitatory synapses. To test the hypothesis that a mutation in SHANK1 contributes to the symptoms of autism, we evaluated Shank1 2/2 null mutant mice for behavioral phenotypes with relevance to autism, focusing on social communication. Ultrasonic vocalizations and the deposition of scent marks appear to be two major modes of mouse communication. Our findings revealed evidence for low levels of ultrasonic vocalizations and scent marks in Shank1 2/2 mice as compared to wildtype Shank1 +/+ littermate controls. Shank1 2/2 pups emitted fewer vocalizations than Shank1 +/+ pups when isolated from mother and littermates. In adulthood, genotype affected scent marking behavior in the presence of female urinary pheromones. Adult Shank1 2/2 males deposited fewer scent marks in proximity to female urine than Shank1 +/+ males. Call emission in response to female urinary pheromones also differed between genotypes. Shank1 +/+ mice changed their calling pattern dependent on previous female interactions, while Shank1 2/2 mice were unaffected, indicating a failure o
Tobias M. Boeckers - One of the best experts on this subject based on the ideXlab platform.
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Altered Intestinal Morphology and Microbiota Composition in the Autism Spectrum Disorders Associated SHANK3 Mouse Model
MDPI AG, 2019Co-Authors: Ann Katrin Sauer, Juergen Bockmann, Tobias M. Boeckers, Konrad Steinestel, Andreas M. GrabruckerAbstract:Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (SHANK) gene-family were identified in patients with ASD, and Shank knock-out mouse models display autism-like phenotypes. SHANK3 proteins are not only expressed in the central nervous system (CNS). Here, we show expression in gastrointestinal (GI) epithelium and report a significantly different GI morphology in SHANK3 knock-out (KO) mice. Further, we detected a significantly altered microbiota composition measured in feces of SHANK3 KO mice that may contribute to inflammatory responses affecting brain development. In line with this, we found higher E. coli lipopolysaccharide levels in liver samples of SHANK3 KO mice, and detected an increase in Interleukin-6 and activated astrocytes in SHANK3 KO mice. We conclude that apart from its well-known role in the CNS, SHANK3 plays a specific role in the GI tract that may contribute to the ASD phenotype by extracerebral mechanisms
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heterogeneity of cell surface glutamate and gaba receptor expression in shank and cntn4 autism mouse models
Frontiers in Molecular Neuroscience, 2018Co-Authors: Christopher Heise, Jonathan M Preuss, Jan C Schroeder, Chiara R Battaglia, Jonas Kolibius, Rebecca Schmid, Peter J H Burbach, Michael R. Kreutz, Tobias M. BoeckersAbstract:Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The SHANK3 gene (and to a lesser degree SHANK2) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the CONTACTIN 4 gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study we used mutant/knock-out mice of Shank2 (Shank2-/-), SHANK3 (SHANK3αβ-/-), and Cntn4 (Cntn4-/-) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of classical several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and NR1GluN1 were analyzed for excitatory synaptic transmission, and the α1 subunit of the GABAA receptor was analyzed for inhibitory synaptic transmission. We found that both Shank2-/- and SHANK3αβ-/- mice exhibit reduced levels of several cell surface glutamate receptors in most of the analyzed brain regions – especially in the striatum and thalamus – when compared to wildtype controls. Interestingly, even though Cntn4-/- mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4-/- mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions.
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Structure of an unconventional SH3 domain from the postsynaptic density protein SHANK3 at ultrahigh resolution.
Biochemical and Biophysical Research Communications, 2017Co-Authors: Srinivas Kumar Ponna, Matti Myllykoski, Tobias M. Boeckers, Petri KursulaAbstract:Abstract The Shank family comprises three large multi-domain proteins playing central roles as protein scaffolds in the neuronal postsynaptic density. The Shank proteins are closely linked to neuropsychiatric diseases, such as autism spectrum disorders. One characteristic domain in the Shank family is the SH3 domain, assumed to play a role in protein-protein interactions; however, no specific ligand binding to any Shank SH3 domain has been described. We solved the crystal structure of the SH3 domain from SHANK3 at sub-atomic resolution. While the structure presents the canonical SH3 domain fold, the binding site for proline-rich peptides is not conserved. In line with this, no binding of Pro-rich sequences by the SHANK3 SH3 domain was observed. Sequence comparisons indicate that all Shank isoforms have similarly lost the classical Pro-rich peptide binding site from the SH3 domain. Whether the corresponding site in the Shank SH3 domains has evolved to bind a non-poly-Pro target sequence is currently not known. Our work provides an intriguing example of the evolution of a well-characterized protein-protein interaction domain within the context of multi-domain protein scaffolds, allowing the conservation of structural features, but losing canonical functional sites. The data are further discussed in light of known mutations in the SH3 domain or its vicinity in the different Shank isoforms.
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SHANK3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of NMDA receptor levels at axon terminals
Journal of Neurochemistry, 2016Co-Authors: Sonja Halbedl, Marisa S. Feiler, Michael Schoen, Tobias M. Boeckers, Michael J. SchmeisserAbstract:Autism-related Shank1, Shank2, and SHANK3 are major postsynaptic scaffold proteins of excitatory glutamatergic synapses. A few studies, however, have already indicated that within a neuron, the presence of Shank family members is not limited to the postsynaptic density. By separating axons from dendrites of developing hippocampal neurons in microfluidic chambers, we show that RNA of all three Shank family members is present within axons. Immunostaining confirms these findings as all three Shanks are indeed found within separated axons and further co-localize with well-known proteins of the presynaptic specialization in axon terminals. Therefore, Shank proteins might not only serve as postsynaptic scaffold proteins, but also play a crucial role during axonal outgrowth and presynaptic development and function. This is supported by our findings that shRNA-mediated knockdown of SHANK3 results in up-regulation of the NMDA receptor subunit GluN1 in axon terminals. Taken together, our findings will have major implications for the future analysis of neuronal Shank biology in both health and disease. Shank1, Shank2, and SHANK3 are major postsynaptic scaffold proteins of excitatory glutamatergic synapses strongly related to several neuropsychiatric disorders. However, a few studies have already implicated a functional role of the Shanks beyond the postsynaptic density (PSD). We here show that all three Shanks are localized in both axons and pre-synaptic specializiations of developing hippocampal neurons in culture. We further provide evidence that SHANK3 is involved in the modulation of NMDA receptor levels at axon terminals. Taken together, our study will open up novel avenues for the future analysis of neuronal Shank biology in both health and disease.
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shank1 and prosap1 shank2 mouse models of autism
Autism-open access, 2012Co-Authors: Michael J. Schmeisser, Tobias M. BoeckersAbstract: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.
Andreas M. Grabrucker - One of the best experts on this subject based on the ideXlab platform.
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Altered Intestinal Morphology and Microbiota Composition in the Autism Spectrum Disorders Associated SHANK3 Mouse Model
MDPI AG, 2019Co-Authors: Ann Katrin Sauer, Juergen Bockmann, Tobias M. Boeckers, Konrad Steinestel, Andreas M. GrabruckerAbstract:Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (SHANK) gene-family were identified in patients with ASD, and Shank knock-out mouse models display autism-like phenotypes. SHANK3 proteins are not only expressed in the central nervous system (CNS). Here, we show expression in gastrointestinal (GI) epithelium and report a significantly different GI morphology in SHANK3 knock-out (KO) mice. Further, we detected a significantly altered microbiota composition measured in feces of SHANK3 KO mice that may contribute to inflammatory responses affecting brain development. In line with this, we found higher E. coli lipopolysaccharide levels in liver samples of SHANK3 KO mice, and detected an increase in Interleukin-6 and activated astrocytes in SHANK3 KO mice. We conclude that apart from its well-known role in the CNS, SHANK3 plays a specific role in the GI tract that may contribute to the ASD phenotype by extracerebral mechanisms
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Prospects of Zinc Supplementation in Autism Spectrum Disorders and Shankopathies Such as Phelan McDermid Syndrome.
Frontiers in Synaptic Neuroscience, 2018Co-Authors: Simone Hagmeyer, Ann Katrin Sauer, Andreas M. GrabruckerAbstract:The loss of one copy of SHANK3 (SH3 and multiple ankyrin repeat domains 3) in humans highly contributes to Phelan McDermid syndrome (PMDS). In addition, SHANK3 was identified as a major autism candidate gene. Interestingly, the protein encoded by the SHANK3 gene is regulated by zinc. While zinc deficiency depletes synaptic pools of SHANK3, increased zinc levels were shown to promote synaptic scaffold formation. Therefore, the hypothesis arises that patients with PMDS and Autism caused by Shankopathies, having one intact copy of SHANK3 left, may benefit from zinc supplementation, as elevated zinc may drive remaining SHANK3 into the post-synaptic density (PSD) and may additional recruit Shank2, a second zinc-dependent member of the SHANK gene family. Further, elevated synaptic zinc levels may modulate E/I ratios affecting other synaptic components such as NMDARs. However, several factors need to be considered in relation to zinc supplementation such as the role of SHANK3 in the gastrointestinal (GI) system-the location of zinc absorption in humans. Therefore, here, we briefly discuss the prospect and impediments of zinc supplementation in disorders affecting SHANK3 such as PMDS and propose a model for most efficacious supplementation.
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Actin-Dependent Alterations of Dendritic Spine Morphology in Shankopathies
Neural Plasticity, 2016Co-Authors: Tasnuva Sarowar, Andreas M. GrabruckerAbstract:Shank proteins (Shank1, Shank2, and SHANK3) act as scaffolding molecules in the postsynaptic density of many excitatory neurons. Mutations in SHANK genes, in particular SHANK2 and SHANK3, lead to autism spectrum disorders (ASD) in both human and mouse models. SHANK3 proteins are made of several domains—the Shank/ProSAP N-terminal (SPN) domain, ankyrin repeats, SH3 domain, PDZ domain, a proline-rich region, and the sterile alpha motif (SAM) domain. Via various binding partners of these domains, SHANK3 is able to bind and interact with a wide range of proteins including modulators of small GTPases such as RICH2, a RhoGAP protein, and βPIX, a RhoGEF protein for Rac1 and Cdc42, actin binding proteins and actin modulators. Dysregulation of all isoforms of Shank proteins, but especially SHANK3, leads to alterations in spine morphogenesis, shape, and activity of the synapse via altering actin dynamics. Therefore, here, we highlight the role of Shank proteins as modulators of small GTPases and, ultimately, actin dynamics, as found in multiple in vitro and in vivo models. The failure to mediate this regulatory role might present a shared mechanism in the pathophysiology of autism-associated mutations, which leads to dysregulation of spine morphogenesis and synaptic signaling.
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autism associated mutations in prosap2 SHANK3 impair synaptic transmission and neurexin neuroligin mediated transsynaptic signaling
The Journal of Neuroscience, 2012Co-Authors: Magali H Arons, Michael Schoen, Tobias M. Boeckers, Andreas M. Grabrucker, Charlotte J Thynne, Juliette E Cheyne, Johanna M Montgomery, Craig C GarnerAbstract:Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/SHANK3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/SHANK3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/SHANK3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin–Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/SHANK3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin–Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/SHANK3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/SHANK3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS.
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amyloid beta protein induced zinc sequestration leads to synaptic loss via dysregulation of the prosap2 SHANK3 scaffold
Molecular Neurodegeneration, 2011Co-Authors: Michael Schoen, Michael J. Schmeisser, Andreas M. Grabrucker, Magali H Arons, Patrick T Udvardi, Nathaniel S Woodling, Katrin I Andreasson, Patrick R Hof, Joseph D. BuxbaumAbstract:Background Memory deficits in Alzheimer's disease (AD) manifest together with the loss of synapses caused by the disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines. However, the underlying molecular mechanisms remain elusive. Since it was shown that ProSAP2/SHANK3 scaffold assembly within the PSD is Zn2+-dependent and that the amyloid beta protein (Aβ) is able to bind Zn2+, we hypothesize that sequestration of Zn2+ ions by Aβ contributes to ProSAP/Shank platform malformation.
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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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, Karl Jakob Vorckel, Rainer K W Schwarting, 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.
Morgan Sheng - One of the best experts on this subject based on the ideXlab platform.
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USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-Dependent Protein Levels.
The Journal of Neuroscience, 2018Co-Authors: Meghan Kerrisk Campbell, Morgan ShengAbstract:Mutations or altered protein levels of SHANK3 are implicated in neurodevelopmental disorders such as Phelan–McDermid syndrome, autism spectrum disorders, and schizophrenia (Guilmatre et al., 2014). Loss of SHANK3 in mouse models results in decreased synapse density and reduction in the levels of multiple synaptic proteins (Jiang and Ehlers, 2013). The family of SHANK scaffolding molecules are among the most heavily ubiquitinated proteins at the postsynaptic density. The ubiquitin-dependent proteasome degradation of SHANK is regulated by synaptic activity and may contribute to activity-dependent synaptic remodeling (Ehlers, 2003; Shin et al., 2012). However, the identity of the specific deubiquitinating enzymes and E3 ligases that regulate SHANK ubiquitination at synapses are unknown. Here we identify USP8/UBPY as a deubiquitinating enzyme that regulates SHANK3 and SHANK1 ubiquitination and protein levels. In primary rat neurons, USP8 enhances SHANK3 and SHANK1 protein levels via deubiquitination and increases dendritic spine density. Additionally, USP8 is essential for changes in SHANK3 protein levels following synaptic activity modulation. These data identify USP8 as a key modulator of SHANK3 downstream of synaptic activity. SIGNIFICANCE STATEMENT Precise regulation of the protein levels of the postsynaptic scaffolding protein SHANK3 is essential for proper neurodevelopment. Mutations of SHANK3 have been identified in Phelan–McDermid syndrome, autism spectrum disorders, and schizophrenia (Guilmatre et al., 2014). In this research, we identify USP8 as a key enzyme that regulates SHANK3 protein levels in neurons. USP8 acts to deubiquitinate SHANK3, which prevents its proteasomal-mediated degradation and enhances overall dendritic spine stability. In the future, the modulation of USP8 deubiquitinating activity could potentially be used to titrate the protein levels of SHANK3 to ameliorate disease.
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Communication Impairments in Mice Lacking Shank1: Reduced Levels of Ultrasonic Vocalizations and Scent Marking Behavior
2013Co-Authors: Markus Wohr, Florence I Roullet, Albert Y Hung, Morgan Sheng, Jacqueline N CrawleyAbstract:Autism is a neurodevelopmental disorder with a strong genetic component. Core symptoms are abnormal reciprocal social interactions, qualitative impairments in communication, and repetitive and stereotyped patterns of behavior with restricted interests. Candidate genes for autism include the SHANK gene family, as mutations in SHANK2 and SHANK3 have been detected in several autistic individuals. SHANK genes code for a family of scaffolding proteins located in the postsynaptic density of excitatory synapses. To test the hypothesis that a mutation in SHANK1 contributes to the symptoms of autism, we evaluated Shank1 2/2 null mutant mice for behavioral phenotypes with relevance to autism, focusing on social communication. Ultrasonic vocalizations and the deposition of scent marks appear to be two major modes of mouse communication. Our findings revealed evidence for low levels of ultrasonic vocalizations and scent marks in Shank1 2/2 mice as compared to wildtype Shank1 +/+ littermate controls. Shank1 2/2 pups emitted fewer vocalizations than Shank1 +/+ pups when isolated from mother and littermates. In adulthood, genotype affected scent marking behavior in the presence of female urinary pheromones. Adult Shank1 2/2 males deposited fewer scent marks in proximity to female urine than Shank1 +/+ males. Call emission in response to female urinary pheromones also differed between genotypes. Shank1 +/+ mice changed their calling pattern dependent on previous female interactions, while Shank1 2/2 mice were unaffected, indicating a failure o
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communication impairments in mice lacking shank1 reduced levels of ultrasonic vocalizations and scent marking behavior
PLOS ONE, 2011Co-Authors: Markus Wohr, Florence I Roullet, Albert Y Hung, Morgan Sheng, Jacqueline N CrawleyAbstract:Autism is a neurodevelopmental disorder with a strong genetic component. Core symptoms are abnormal reciprocal social interactions, qualitative impairments in communication, and repetitive and stereotyped patterns of behavior with restricted interests. Candidate genes for autism include the SHANK gene family, as mutations in SHANK2 and SHANK3 have been detected in several autistic individuals. SHANK genes code for a family of scaffolding proteins located in the postsynaptic density of excitatory synapses. To test the hypothesis that a mutation in SHANK1 contributes to the symptoms of autism, we evaluated Shank1−/− null mutant mice for behavioral phenotypes with relevance to autism, focusing on social communication. Ultrasonic vocalizations and the deposition of scent marks appear to be two major modes of mouse communication. Our findings revealed evidence for low levels of ultrasonic vocalizations and scent marks in Shank1−/− mice as compared to wildtype Shank1+/+ littermate controls. Shank1−/− pups emitted fewer vocalizations than Shank1+/+ pups when isolated from mother and littermates. In adulthood, genotype affected scent marking behavior in the presence of female urinary pheromones. Adult Shank1−/− males deposited fewer scent marks in proximity to female urine than Shank1+/+ males. Call emission in response to female urinary pheromones also differed between genotypes. Shank1+/+ mice changed their calling pattern dependent on previous female interactions, while Shank1−/− mice were unaffected, indicating a failure of Shank1−/− males to learn from a social experience. The reduced levels of ultrasonic vocalizations and scent marking behavior in Shank1−/− mice are consistent with a phenotype relevant to social communication deficits in autism.
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sociability and motor functions in shank1 mutant mice
Brain Research, 2011Co-Authors: Jill L Silverman, Albert Y Hung, Charlotte L Barkan, Seda S Tolu, Sarah M Turner, Roheeni Saxena, Morgan Sheng, Jacqueline N CrawleyAbstract:Autism is a neurodevelopmental disorder characterized by aberrant reciprocal social interactions, impaired communication, and repetitive behaviors. While the etiology remains unclear, strong evidence exists for a genetic component, and several synaptic genes have been implicated. SHANK genes encode a family of synaptic scaffolding proteins located postsynaptically on excitatory synapses. Mutations in SHANK genes have been detected in several autistic individuals. To understand the consequences of SHANK mutations relevant to the diagnostic and associated symptoms of autism, comprehensive behavioral phenotyping on a line of Shank1 mutant mice was conducted on multiple measures of social interactions, social olfaction, repetitive behaviors, anxiety-related behaviors, motor functions, and a series of control measures for physical abilities. Results from our comprehensive behavioral phenotyping battery indicated that adult Shank1 null mutant mice were similar to their wildtype and heterozygous littermates on standardized measures of general health, neurological reflexes and sensory skills. Motor functions were reduced in the null mutants on open field activity, rotarod, and wire hang, replicating and extending previous findings (Hung et al., 2008). A partial anxiety-like phenotype was detected in the null mutants in some components of the light ↔ dark task, as previously reported (Hung et al., 2008) but not in the elevated plus-maze. Juvenile reciprocal social interactions did not differ across genotypes. Interpretation of adult social approach was confounded by a lack of normal sociability in wildtype and heterozygous littermates. All genotypes were able to discriminate social odors on an olfactory habituation/dishabituation task. All genotypes displayed relatively high levels of repetitive self-grooming. Our findings support the interpretation that Shank1 null mice do not demonstrate autism-relevant social interaction deficits, but confirm and extend a role for Shank1 in motor functions.
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Characterization of the Shank Family of Synaptic Proteins MULTIPLE GENES, ALTERNATIVE SPLICING, AND DIFFERENTIAL EXPRESSION IN BRAIN AND DEVELOPMENT
Journal of Biological Chemistry, 1999Co-Authors: Scott Naisbitt, Jiyoung Yoon, Jong-ik Hwang, Morgan ShengAbstract:Abstract Shank1, Shank2, and SHANK3 constitute a family of proteins that may function as molecular scaffolds in the postsynaptic density (PSD). Shank directly interacts with GKAP and Homer, thus potentially bridging the N-methyl-d-aspartate receptor-PSD-95-GKAP complex and the mGluR-Homer complex in synapses (Naisbitt, S., Kim, E., Tu, J. C., Xiao, B., Sala, S., Valtschanoff, J., Weinberg, R. J., Worley, P. F., and Sheng, M. (1999) Neuron 23, 569–582; Tu, J. C., Xiao, B., Naisbitt, S., Yuan, J. P., Petralia, R. S., Brakeman, P., Doan, A., Aakalu, V. K., Lanahan, A. A., Sheng, M., and Worley, P. F. (1999) Neuron 23, 583–592). Shank contains multiple domains for protein-protein interaction including ankyrin repeats, an SH3 domain, a PSD-95/Dlg/ZO-1 domain, a sterile α motif domain, and a proline-rich region. By characterizingShank cDNA clones and RT-PCR products, we found that there are four sites for alternative splicing in Shank1 and another four sites in Shank2, some of which result in deletion of specific domains of the Shank protein. In addition, the expression of the splice variants is differentially regulated in different regions of rat brain during development. Immunoblot analysis of Shank proteins in rat brain using five different Shank antibodies reveals marked heterogeneity in size (120–240 kDa) and differential spatiotemporal expression. Shank1 immunoreactivity is concentrated at excitatory synaptic sites in adult brain, and the punctate staining of Shank1 is seen in developing rat brains as early as postnatal day 7. These results suggest that alternative splicing in the Shank family may be a mechanism that regulates the molecular structure of Shank and the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain.
