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 et/ou numérique 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 et/ou numérique] / 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

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

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

Public ISBD [article]  inMolecular Autism > (June 2015) . - p.1-10 Titre : Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice Type de document : Texte imprimé et/ou numérique Auteurs : Neha UPPAL, Auteur ; Rishi PURI, Auteur ; Frank YUK, Auteur ; William G. M. JANSSEN, Auteur ; Ozlem BOZDAGI-GUNAL, Auteur ; Hala HARONY-NICOLAS, Auteur ; Dara L. DICKSTEIN, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur Article en page(s) : p.1-10 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The genetics of autism spectrum disorder (hereafter referred to as “autism”) are rapidly unfolding, with a significant increase in the identification of genes implicated in the disorder. Many of these genes are part of a complex landscape of genetic variants that are thought to act together to cause the behavioral phenotype associated with autism. One of the few single-locus causes of autism involves a mutation in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. Previous electrophysiological studies in mice with Shank3 mutations demonstrated impairment in synaptic long-term potentiation, suggesting a potential disruption at the synapse. En ligne : http://dx.doi.org/10.1186/s13229-015-0036-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice [Texte imprimé et/ou numérique] / Neha UPPAL, Auteur ; Rishi PURI, Auteur ; Frank YUK, Auteur ; William G. M. JANSSEN, Auteur ; Ozlem BOZDAGI-GUNAL, Auteur ; Hala HARONY-NICOLAS, Auteur ; Dara L. DICKSTEIN, Auteur ; Joseph D. BUXBAUM, Auteur ; Patrick R. HOF, Auteur . - p.1-10. Langues : Anglais (eng) in Molecular Autism > (June 2015) . - p.1-10 Index. décimale : PER Périodiques Résumé : The genetics of autism spectrum disorder (hereafter referred to as “autism”) are rapidly unfolding, with a significant increase in the identification of genes implicated in the disorder. Many of these genes are part of a complex landscape of genetic variants that are thought to act together to cause the behavioral phenotype associated with autism. One of the few single-locus causes of autism involves a mutation in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. Previous electrophysiological studies in mice with Shank3 mutations demonstrated impairment in synaptic long-term potentiation, suggesting a potential disruption at the synapse. En ligne : http://dx.doi.org/10.1186/s13229-015-0036-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

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