scholarly journals Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah Jacot-Descombes ◽  
Neha U. Keshav ◽  
Dara L. Dickstein ◽  
Bridget Wicinski ◽  
William G. M. Janssen ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Rat Model ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Dendritic Morphology ◽  
Scaffolding Protein ◽  
Spine Density ◽  
Synaptic Structure ◽  
Synaptic Ultrastructure ◽  
Behavioral Impairments

Abstract 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.

scholarly journals Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

2020 ◽  
Author(s):  
Sarah Jacot-Descombes ◽  
Neha U Keshav ◽  
Dara L. Dickstein ◽  
Bridget Wicinski ◽  
William G. M. Janssen ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Rat Model ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Dendritic Morphology ◽  
Scaffolding Protein ◽  
Spine Density ◽  
Synaptic Structure ◽  
Synaptic Ultrastructure ◽  
Behavioral Impairments

Abstract 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 the 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.

scholarly journals Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

2020 ◽  
Author(s):  
Sarah Jacot-Descombes ◽  
Neha U Keshav ◽  
Dara L. Dickstein ◽  
Bridget Wicinski ◽  
William G. M. Janssen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Rat Model ◽  
Postsynaptic Density ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Head Diameter ◽  
Density Area ◽  
Synaptic Ultrastructure

Abstract Background Deletion or mutations of SHANK3 lead to Phelan-McDermid syndrome and monogenic forms of autism spectrum disorder. SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered dendritic and spine morphology in the hippocampus, cerebellum and striatum have been associated with behavioral impairments in various Shank3-deficient animal models. Given the attentional deficit reported in these animals, our study explored whether deficiency of Shank3 in a rat model alters synaptic ultrastructure in the medial prefrontal cortex. Methods We used electron microscopy to determine the density of asymmetric synapses in layer III excitatory neurons of the medial prefrontal cortex in 5 week-old Shank3-homozygous knockout ( Shank3 -KO), heterozygous ( Shank3 -Het), and wild-type (WT) rats. We also measured postsynaptic density length, postsynaptic density area, and head diameter of dendritic spines at these synapses. Results All three groups had comparable synapse density and postsynaptic density length. Spine head diameter of Shank3 -Het rats, but not Shank3 -KO, was larger than WT rats. Shank3 -Het rats had wider head diameter in non-perforated synapses compared to WT and Shank3 -KO rats. The total postsynaptic density area was significantly larger in Shank3 -Het rats compared to Shank3 -KO and WT rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the medial prefrontal cortex 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 as such, would only model the effect of the mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, this study focused only on synaptic ultrastructure in male Shank3 -deficient rats. Conclusions We observed increased head diameter and postsynaptic density area in rats heterozygous for Shank3 deficiency. Further investigations of the mechanisms leading to altered synaptic ultrastructure in this animal model will enable us to understand better the role that Shank3 protein plays in autism spectrum disorder and Phelan-McDermid syndrome.

scholarly journals Changes in the Number and Morphology of Dendritic Spines in the Hippocampus and Prefrontal Cortex of the C58/J Mouse Model of Autism

2021 ◽  
Vol 15 ◽  
Author(s):  
Isabel Barón-Mendoza ◽  
Emely Maqueda-Martínez ◽  
Mónica Martínez-Marcial ◽  
Marisol De la Fuente-Granada ◽  
Margarita Gómez-Chavarin ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Dendritic Spines ◽  
Metabotropic Glutamate Receptor ◽  
Inbred Mouse ◽  
Inbred Mouse Strain ◽  
Stereotyped Behavior ◽  
Autism Spectrum ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Spine Density

Autism spectrum disorder (ASD) has a broad range of neurobiological characteristics, including alterations in dendritic spines, where approximately 90% of excitatory synapses occur. Therefore, changes in their number or morphology would be related to atypical brain communication. The C58/J inbred mouse strain displays low sociability, impaired communication, and stereotyped behavior; hence, it is considered among the animal models suitable for the study of idiopathic autism. Thus, this study aimed to evaluate the dendritic spine differences in the hippocampus and the prefrontal cortex of C58/J mice. We found changes in the number of spines and morphology in a brain region-dependent manner: a subtle decrease in spine density in the prefrontal cortex, higher frequency of immature phenotype spines characterized by filopodia-like length or small morphology, and a lower number of mature phenotype spines with mushroom-like or wide heads in the hippocampus. Moreover, an in silico analysis showed single nucleotide polymorphisms (SNPs) at genes collectively involved in regulating structural plasticity with a likely association with ASD, including MAP1A (Microtubule-Associated Protein 1A), GRM7 (Metabotropic Glutamate Receptor, 7), ANKRD11 (Ankyrin Repeat Domain 11), and SLC6A4 (Solute Carrier Family 6, member 4), which might support the relationship between the C58/J strain genome, an autistic-like behavior, and the observed anomalies in the dendritic spines.

Prefrontal cortex, hippocampus, and basolateral amygdala plasticity in a rat model of autism spectrum

Synapse ◽  
2014 ◽  
Vol 68 (10) ◽  
pp. 468-473 ◽  
Author(s):  
Nuvia Sosa-Díaz ◽  
Maria Elena Bringas ◽  
Marco Atzori ◽  
Gonzalo Flores
Keyword(s):  
Prefrontal Cortex ◽  
Rat Model ◽  
Basolateral Amygdala ◽  
Autism Spectrum

scholarly journals Gene Dosage- and Age-Dependent Differential Transcriptomic Changes in the Prefrontal Cortex of Shank2-Mutant Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Seungjoon Lee ◽  
Hyojin Kang ◽  
Hwajin Jung ◽  
Eunjoon Kim ◽  
Eunee Lee
Keyword(s):  
Prefrontal Cortex ◽  
Gene Dosage ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Mitochondrial Genes ◽  
Mutant Mice ◽  
Scaffolding Protein ◽  
Age Dependent ◽  
Gaba Neuron ◽  
Transcriptomic Changes

Shank2 is an abundant postsynaptic scaffolding protein that is known to regulate excitatory synapse assembly and synaptic transmission and has been implicated in various neurodevelopmental disorders, including autism spectrum disorders (ASD). Previous studies on Shank2-mutant mice provided mechanistic insights into their autistic-like phenotypes, but it remains unclear how transcriptomic patterns are changed in brain regions of the mutant mice in age- and gene dosage-dependent manners. To this end, we performed RNA-Seq analyses of the transcripts from the prefrontal cortex (PFC) of heterozygous and homozygous Shank2-mutant mice lacking exons 6 and 7 at juvenile (week 3) and adult (week 12) stages. Juvenile heterozygous Shank2-mutant mice showed upregulation of glutamate synapse-related genes, downregulation of ribosomal and mitochondrial genes, and transcriptomic changes that are opposite to those observed in ASD (anti-ASD) such as upregulation of ASD_down (downregulated in ASD), GABA neuron-related, and oligodendrocyte-related genes. Juvenile homozygous Shank2 mice showed upregulation of chromatin-related genes and transcriptomic changes that are in line with those occurring in ASD (pro-ASD) such as downregulation of ASD_down, GABA neuron-related, and oligodendrocyte-related genes. Adult heterozygous and homozygous Shank2-mutant mice both exhibited downregulation of ribosomal and mitochondrial genes and pro-ASD transcriptomic changes. Therefore, the gene dosage- and age-dependent effects of Shank2 deletions in mice include differential transcriptomic changes across distinct functional contexts, including synapses, chromatin, ribosomes, mitochondria, GABA neurons, and oligodendrocytes.

scholarly journals Effectiveness of Equine-Assisted Activities and Therapies for Improving Adaptive Behavior and Motor Function in Autism Spectrum Disorder

2021 ◽  
Vol 10 (8) ◽  
pp. 1726
Author(s):  
Leonardo Zoccante ◽  
Michele Marconi ◽  
Marco Luigi Ciceri ◽  
Silvia Gagliardoni ◽  
Luigi Alberto Gozzi ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Motor Function ◽  
Adaptive Behavior ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Parental Distress ◽  
Effective Option ◽  
The Impact ◽  
Equine Assisted

Equine-assisted activities and therapies (EAAT) have been suggested to improve adaptive behavior, and possibly motor function, in autism spectrum disorder (ASD). This study investigated the effects of EAAT on adaptive behavior and motor function in 15 children with ASD (13 males) aged 7–15 years as well as the impact of EAAT on the magnitude of stress in the parent–child system and the evolution in the child interaction with both the trained therapist and the therapeutic animal through the 20 weekly sessions of EAAT. EAAT were associated with greater adaptive behavior and coordination (all p ≤ 0.01) as well as a progressive improvement in the child’s abilities to respond to the increasing complexity of such form of positive behavioral support (all p < 0.001). However, EAAT did not prove to be effective in reducing parental distress. Collectively, preliminary evidence presented here may have important public health implications and gives reason to hope that EAAT could possibly be an effective option in ASD, warranting further investigation of its potential benefits in clinical trials among larger samples.

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