Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats / Sarah JACOT-DESCOMBES in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) Titre : Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats Type de document : texte imprimé Auteurs : Sarah JACOT-DESCOMBES, Auteur ; Neha U. KESHAV, Auteur ; Dara L. DICKSTEIN, Auteur ; Bridget WICINSKI, Auteur ; William G.M. JANSSEN, Auteur ; Liam L. HIESTER, Auteur ; Edward K. SARFO, Auteur ; Tahia WARDA, Auteur ; Matthew M. FAM, Auteur ; Hala HARONY-NICOLAS, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur ; Merina VARGHESE, Auteur Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Electron microscopy  Phelan–McDermid syndrome  Synapse morphology Index. décimale : PER Périodiques Résumé : BACKGROUND: Deletion or mutations of SHANK3 lead to Phelan-McDermid syndrome and monogenic forms of autism spectrum disorder (ASD). SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency of Shank3 in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC). METHODS: We assessed dendrite and spine morphology and spine density in mPFC layer III neurons in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses. RESULTS: Basal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes in Shank3-Het compared to WT and Shank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses in Shank3-Het rats, but not Shank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger in Shank3-Het rats compared to Shank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan-McDermid syndrome. LIMITATIONS: The Shank3 deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in male Shank3-deficient rats. CONCLUSIONS: We observed increased HD and PSD area in Shank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan-McDermid syndrome. En ligne : http://dx.doi.org/10.1186/s13229-020-00393-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438 [article] Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats [texte imprimé] / Sarah JACOT-DESCOMBES, Auteur ; Neha U. KESHAV, Auteur ; Dara L. DICKSTEIN, Auteur ; Bridget WICINSKI, Auteur ; William G.M. JANSSEN, Auteur ; Liam L. HIESTER, Auteur ; Edward K. SARFO, Auteur ; Tahia WARDA, Auteur ; Matthew M. FAM, Auteur ; Hala HARONY-NICOLAS, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur ; Merina VARGHESE, Auteur. Langues : Anglais (eng) in Molecular Autism > 11 (2020) Mots-clés : Autism spectrum disorder  Electron microscopy  Phelan–McDermid syndrome  Synapse morphology Index. décimale : PER Périodiques Résumé : BACKGROUND: Deletion or mutations of SHANK3 lead to Phelan-McDermid syndrome and monogenic forms of autism spectrum disorder (ASD). SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency of Shank3 in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC). METHODS: We assessed dendrite and spine morphology and spine density in mPFC layer III neurons in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses. RESULTS: Basal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes in Shank3-Het compared to WT and Shank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses in Shank3-Het rats, but not Shank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger in Shank3-Het rats compared to Shank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan-McDermid syndrome. LIMITATIONS: The Shank3 deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in male Shank3-deficient rats. CONCLUSIONS: We observed increased HD and PSD area in Shank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan-McDermid syndrome. En ligne : http://dx.doi.org/10.1186/s13229-020-00393-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438

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 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] / 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 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] / 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 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] / 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 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] / 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)  

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Reduced brain volume and white matter alterations in Shank3-deficient rats / Carla E.M. GOLDEN in Autism Research, 14-9 (September 2021)  

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Rigor in science and science reporting: updated guidelines for submissions to Molecular Autism / Joseph D. BUXBAUM in Molecular Autism, 10 (2019)  

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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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