Autism : neuropathology, alterations of the GABAergic system, and animal models / Christoph SCHMITZ

Public ISBD contenu dans The GABA in Autism and Related Disorders / Dirk M. DHOSSCHE Titre : Autism : neuropathology, alterations of the GABAergic system, and animal models Type de document : Texte imprimé et/ou numérique Auteurs : Christoph SCHMITZ, Auteur ; Imke A. J. VAN KOOTEN, Auteur ; Patrick R. HOF, Auteur ; Herman VAN ENGELAND, Auteur ; Paul H. PATTERSON, Auteur ; Harry W. M. STEINBUSCH, Auteur Année de publication : 2005 Importance : p.1-26 Langues : Anglais (eng) Mots-clés : Acide ?-aminobutyrique Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=668 contenu dans The GABA in Autism and Related Disorders / Dirk M. DHOSSCHE Autism : neuropathology, alterations of the GABAergic system, and animal models [Texte imprimé et/ou numérique] / Christoph SCHMITZ, Auteur ; Imke A. J. VAN KOOTEN, Auteur ; Patrick R. HOF, Auteur ; Herman VAN ENGELAND, Auteur ; Paul H. PATTERSON, Auteur ; Harry W. M. STEINBUSCH, Auteur . - 2005 . - p.1-26. Langues : Anglais (eng) Mots-clés : Acide ?-aminobutyrique Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=668

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Discrete Cortical Neuropathology in Autism Spectrum Disorders / Neha UPPAL

Public ISBD in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM Titre : Discrete Cortical Neuropathology in Autism Spectrum Disorders Type de document : Texte imprimé et/ou numérique Auteurs : Neha UPPAL, Auteur ; Patrick R. HOF, Auteur Année de publication : 2013 Importance : p.313-325 Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) are the most inheritable of psychiatric disorders, although precise genetic alterations have only been identified in about 20% of cases. The major impact of the condition on the development and social integration of affected children has led to a marked increase in research efforts focusing on the possible roles of neuropathological processes underlying it. This chapter provides an overview of the literature on the cortical neuropathology of ASD. Postmortem studies are pivotal for cell-level exploration, especially in the context of brain regions which consistently show altered patterns of activation in functional magnetic resonance imaging studies. Cortical alterations known to occur in ASD are reviewed, including abnormalities in neuronal morphology, neurotransmitter systems, and cytoarchitectural organization. We focus in particular on abnormalities of the prefrontal cortex, the inferior frontal cortex, fusiform gyrus, the insular cortex, the cingulate cortex, and the hippocampus. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189 in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM Discrete Cortical Neuropathology in Autism Spectrum Disorders [Texte imprimé et/ou numérique] / Neha UPPAL, Auteur ; Patrick R. HOF, Auteur . - 2013 . - p.313-325. Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) are the most inheritable of psychiatric disorders, although precise genetic alterations have only been identified in about 20% of cases. The major impact of the condition on the development and social integration of affected children has led to a marked increase in research efforts focusing on the possible roles of neuropathological processes underlying it. This chapter provides an overview of the literature on the cortical neuropathology of ASD. Postmortem studies are pivotal for cell-level exploration, especially in the context of brain regions which consistently show altered patterns of activation in functional magnetic resonance imaging studies. Cortical alterations known to occur in ASD are reviewed, including abnormalities in neuronal morphology, neurotransmitter systems, and cytoarchitectural organization. We focus in particular on abnormalities of the prefrontal cortex, the inferior frontal cortex, fusiform gyrus, the insular cortex, the cingulate cortex, and the hippocampus. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189

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Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication / Ozlem BOZDAGI in Molecular Autism, (December 2010)  

Public ISBD [article]  inMolecular Autism > (December 2010) . - 47 p. Titre : Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication Type de document : Texte imprimé et/ou numérique Auteurs : Ozlem BOZDAGI, Auteur ; Takeshi SAKURAI, Auteur ; Danae PAPAPETROU, Auteur ; Xiaobin WANG, Auteur ; Dara L. DICKSTEIN, Auteur ; Nagahide TAKAHASHI, Auteur ; Yuji KAJIWARA, Auteur ; Mu YANG, Auteur ; Adam M. KATZ, Auteur ; Maria Luisa SCATTONI, Auteur ; Mark J. HARRIS, Auteur ; Roheeni SAXENA, Auteur ; Jill L. SILVERMAN, Auteur ; Jacqueline N. CRAWLEY, Auteur ; Qiang ZHOU, Auteur ; Patrick R. HOF, Auteur ; Joseph D. BUXBAUM, Auteur Année de publication : 2010 Article en page(s) : 47 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. Methods We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. Results In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with theta-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. Conclusions We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes. En ligne : http://dx.doi.org/10.1186/2040-2392-1-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=114 [article] Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication [Texte imprimé et/ou numérique] / Ozlem BOZDAGI, Auteur ; Takeshi SAKURAI, Auteur ; Danae PAPAPETROU, Auteur ; Xiaobin WANG, Auteur ; Dara L. DICKSTEIN, Auteur ; Nagahide TAKAHASHI, Auteur ; Yuji KAJIWARA, Auteur ; Mu YANG, Auteur ; Adam M. KATZ, Auteur ; Maria Luisa SCATTONI, Auteur ; Mark J. HARRIS, Auteur ; Roheeni SAXENA, Auteur ; Jill L. SILVERMAN, Auteur ; Jacqueline N. CRAWLEY, Auteur ; Qiang ZHOU, Auteur ; Patrick R. HOF, Auteur ; Joseph D. BUXBAUM, Auteur . - 2010 . - 47 p. Langues : Anglais (eng) in Molecular Autism > (December 2010) . - 47 p. Index. décimale : PER Périodiques Résumé : SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. Methods We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. Results In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with theta-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. Conclusions We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes. En ligne : http://dx.doi.org/10.1186/2040-2392-1-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=114

Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism / Neha UPPAL in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism Type de document : Texte imprimé et/ou numérique Auteurs : Neha UPPAL, Auteur ; Isabella GIANATIEMPO, Auteur ; Bridget WICINSKI, Auteur ; James SCHMEIDLER, Auteur ; Helmut HEINSEN, Auteur ; Christoph SCHMITZ, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : While most neuropathologic studies focus on regions involved in behavioral abnormalities in autism, it is also important to identify whether areas that appear functionally normal are devoid of pathologic alterations. In this study we analyzed the posteroinferior occipitotemporal gyrus, an extrastriate area not considered to be affected in autism. This area borders the fusiform gyrus, which is known to exhibit functional and cellular abnormalities in autism.FINDINGS:No studies have implicated posteroinferior occipitotemporal gyrus dysfunction in autism, leading us to hypothesize that neuropathology would not occur in this area. We indeed observed no significant differences in pyramidal neuron number or size in layers III, V, and VI in seven pairs of autism and controls. These findings are consistent with the hypothesis that neuropathology is unique to areas involved in stereotypies and social and emotional behaviors, and support the specificity of the localization of pathology in the fusiform gyrus. En ligne : http://dx.doi.org/10.1186/2040-2392-5-17 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism [Texte imprimé et/ou numérique] / Neha UPPAL, Auteur ; Isabella GIANATIEMPO, Auteur ; Bridget WICINSKI, Auteur ; James SCHMEIDLER, Auteur ; Helmut HEINSEN, Auteur ; Christoph SCHMITZ, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : While most neuropathologic studies focus on regions involved in behavioral abnormalities in autism, it is also important to identify whether areas that appear functionally normal are devoid of pathologic alterations. In this study we analyzed the posteroinferior occipitotemporal gyrus, an extrastriate area not considered to be affected in autism. This area borders the fusiform gyrus, which is known to exhibit functional and cellular abnormalities in autism.FINDINGS:No studies have implicated posteroinferior occipitotemporal gyrus dysfunction in autism, leading us to hypothesize that neuropathology would not occur in this area. We indeed observed no significant differences in pyramidal neuron number or size in layers III, V, and VI in seven pairs of autism and controls. These findings are consistent with the hypothesis that neuropathology is unique to areas involved in stereotypies and social and emotional behaviors, and support the specificity of the localization of pathology in the fusiform gyrus. En ligne : http://dx.doi.org/10.1186/2040-2392-5-17 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features / Joseph D. BUXBAUM in Molecular Autism, (February 2012)  

Public ISBD [article]  inMolecular Autism > (February 2012) . - 24 p. Titre : Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features Type de document : Texte imprimé et/ou numérique Auteurs : Joseph D. BUXBAUM, Auteur ; Catalina BETANCUR, Auteur ; Ozlem BOZDAGI, Auteur ; Nathan P. DORR, Auteur ; Gregory A. ELDER, Auteur ; Patrick R. HOF, Auteur Année de publication : 2012 Article en page(s) : 24 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitute useful phenotypes in ASD models. Methods To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes. Findings We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1) Changes in brain and neuronal morphology; (2) electrophysiological changes; (3) neurological changes; and (4) higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms. Conclusions The results indicated that mutations in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-3-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=153 [article] Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features [Texte imprimé et/ou numérique] / Joseph D. BUXBAUM, Auteur ; Catalina BETANCUR, Auteur ; Ozlem BOZDAGI, Auteur ; Nathan P. DORR, Auteur ; Gregory A. ELDER, Auteur ; Patrick R. HOF, Auteur . - 2012 . - 24 p. Langues : Anglais (eng) in Molecular Autism > (February 2012) . - 24 p. Index. décimale : PER Périodiques Résumé : Background There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitute useful phenotypes in ASD models. Methods To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes. Findings We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1) Changes in brain and neuronal morphology; (2) electrophysiological changes; (3) neurological changes; and (4) higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms. Conclusions The results indicated that mutations in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-3-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=153

The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM

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Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice / Neha UPPAL in Molecular Autism, (June 2015)  

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