A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum / Taesun YOO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 19 p. Titre : A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum Type de document : Texte imprimé et/ou numérique Auteurs : Taesun YOO, Auteur ; Sun-Gyun KIM, Auteur ; Soo Hyun YANG, Auteur ; Hyun KIM, Auteur ; Eunjoon KIM, Auteur ; Soo Young KIM, Auteur Article en page(s) : 19 p. Langues : Anglais (eng) Mots-clés : Autism  Locomotion  psd-93  Self-grooming  Social interaction  Spiny projection Neurons  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. METHODS: Mice lacking exon 14 of the Dlg2 gene (Dlg2(-/-) mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. RESULTS: Dlg2(-/-) mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2(-/-) mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2(-/-) dorsolateral striatum was significantly reduced. CONCLUSION: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2. En ligne : http://dx.doi.org/10.1186/s13229-020-00324-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum [Texte imprimé et/ou numérique] / Taesun YOO, Auteur ; Sun-Gyun KIM, Auteur ; Soo Hyun YANG, Auteur ; Hyun KIM, Auteur ; Eunjoon KIM, Auteur ; Soo Young KIM, Auteur . - 19 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 19 p. Mots-clés : Autism  Locomotion  psd-93  Self-grooming  Social interaction  Spiny projection Neurons  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. METHODS: Mice lacking exon 14 of the Dlg2 gene (Dlg2(-/-) mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. RESULTS: Dlg2(-/-) mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2(-/-) mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2(-/-) dorsolateral striatum was significantly reduced. CONCLUSION: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2. En ligne : http://dx.doi.org/10.1186/s13229-020-00324-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Enhanced fear limits behavioral flexibility in Shank2-deficient mice / Miru YUN in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 40 p. Titre : Enhanced fear limits behavioral flexibility in Shank2-deficient mice Type de document : Texte imprimé et/ou numérique Auteurs : Miru YUN, Auteur ; Eunjoon KIM, Auteur ; Min Whan JUNG, Auteur Article en page(s) : 40 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics/psychology  Conditioning, Classical  Disease Models, Animal  Fear  Male  Mice  Mice, Knockout  Nerve Tissue Proteins/genetics  Water  Classical conditioning  Reversal learning  Shank2 Index. décimale : PER Périodiques Résumé : BACKGROUND: A core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD. METHODS: We compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6 Âul) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice. RESULTS: Male, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards. LIMITATIONS: We examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated. CONCLUSIONS: Our results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00518-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Enhanced fear limits behavioral flexibility in Shank2-deficient mice [Texte imprimé et/ou numérique] / Miru YUN, Auteur ; Eunjoon KIM, Auteur ; Min Whan JUNG, Auteur . - 40 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 40 p. Mots-clés : Animals  Autism Spectrum Disorder/genetics/psychology  Conditioning, Classical  Disease Models, Animal  Fear  Male  Mice  Mice, Knockout  Nerve Tissue Proteins/genetics  Water  Classical conditioning  Reversal learning  Shank2 Index. décimale : PER Périodiques Résumé : BACKGROUND: A core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD. METHODS: We compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6 Âul) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice. RESULTS: Male, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards. LIMITATIONS: We examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated. CONCLUSIONS: Our results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00518-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

Mutations in Synaptic Adhesion Molecules / Jaewon KO  

Public ISBD in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA Titre : Mutations in Synaptic Adhesion Molecules Type de document : Texte imprimé et/ou numérique Auteurs : Jaewon KO, Auteur ; Caterina MONTANI, Auteur ; Eunjoon KIM, Auteur ; Carlo SALA, Auteur Année de publication : 2016 Importance : p.161-175 Langues : Anglais (eng) Mots-clés : Excitatory synapse  Inhibitory synapse  Neurodevelopmental diseases  Postsynaptic density  Presynapse  Synapse formation Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Synaptic connections are established between neurons during development of the nervous system after axon path finding and dendrite development. Synapse development is mediated by specific synaptic cell adhesion molecules (SCAMs) that accumulate at pre- and postsynaptic sites and trigger synaptic differentiation through interactions with intra- and extracellular proteins. These interactions are essential to align pre- and postsynaptic specializations and to couple the sites of cell-to-cell adhesion to the cytoskeletal and signaling complexes required to recruit and recycle presynaptic vesicles, components of exo- and endocytic zones, and postsynaptic receptors. Not surprisingly, it has been demonstrated that in humans, deletions or mutations in some of the SCAM genes are associated with several neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, and schizophrenia, although the exact connection between genetic background and biochemical mechanisms by which these mutations contribute to the diseases has been only partially revealed. This chapter describes the multiple functions and associated synaptic alterations of the SCAM genes found mutated in neurodevelopmental diseases. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00011-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA Mutations in Synaptic Adhesion Molecules [Texte imprimé et/ou numérique] / Jaewon KO, Auteur ; Caterina MONTANI, Auteur ; Eunjoon KIM, Auteur ; Carlo SALA, Auteur . - 2016 . - p.161-175. Langues : Anglais (eng) Mots-clés : Excitatory synapse  Inhibitory synapse  Neurodevelopmental diseases  Postsynaptic density  Presynapse  Synapse formation Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Synaptic connections are established between neurons during development of the nervous system after axon path finding and dendrite development. Synapse development is mediated by specific synaptic cell adhesion molecules (SCAMs) that accumulate at pre- and postsynaptic sites and trigger synaptic differentiation through interactions with intra- and extracellular proteins. These interactions are essential to align pre- and postsynaptic specializations and to couple the sites of cell-to-cell adhesion to the cytoskeletal and signaling complexes required to recruit and recycle presynaptic vesicles, components of exo- and endocytic zones, and postsynaptic receptors. Not surprisingly, it has been demonstrated that in humans, deletions or mutations in some of the SCAM genes are associated with several neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, and schizophrenia, although the exact connection between genetic background and biochemical mechanisms by which these mutations contribute to the diseases has been only partially revealed. This chapter describes the multiple functions and associated synaptic alterations of the SCAM genes found mutated in neurodevelopmental diseases. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00011-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301

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