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.

The elongation factor eEF1A2 controls translation and actin dynamics in dendritic spines

2021 ◽  
Vol 14 (691) ◽  
pp. eabf5594
Author(s):  
Mònica B. Mendoza ◽  
Sara Gutierrez ◽  
Raúl Ortiz ◽  
David F. Moreno ◽  
Maria Dermit ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Molecular Mechanisms ◽  
Metabotropic Glutamate Receptor ◽  
Elongation Factor ◽  
Mrna Translation ◽  
Actin Dynamics ◽  
Dependent Manner ◽  
Spine Density ◽  
Translation Elongation Factor ◽  
Translation Elongation

Synaptic plasticity involves structural modifications in dendritic spines that are modulated by local protein synthesis and actin remodeling. Here, we investigated the molecular mechanisms that connect synaptic stimulation to these processes. We found that the phosphorylation of isoform-specific sites in eEF1A2—an essential translation elongation factor in neurons—is a key modulator of structural plasticity in dendritic spines. Expression of a nonphosphorylatable eEF1A2 mutant stimulated mRNA translation but reduced actin dynamics and spine density. By contrast, a phosphomimetic eEF1A2 mutant exhibited decreased association with F-actin and was inactive as a translation elongation factor. Activation of metabotropic glutamate receptor signaling triggered transient dissociation of eEF1A2 from its regulatory guanine exchange factor (GEF) protein in dendritic spines in a phosphorylation-dependent manner. We propose that eEF1A2 establishes a cross-talk mechanism that coordinates translation and actin dynamics during spine remodeling.

scholarly journals Dendritic Spines in Depression: What We Learned from Animal Models

2016 ◽  
Vol 2016 ◽  
pp. 1-26 ◽  
Author(s):  
Hui Qiao ◽  
Ming-Xing Li ◽  
Chang Xu ◽  
Hui-Bin Chen ◽  
Shu-Cheng An ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Chronic Stress ◽  
Dendritic Spines ◽  
Mild Stress ◽  
Spine Density ◽  
Chronic Social Defeat Stress ◽  
Underlying Mechanisms ◽  
Dendritic Atrophy ◽  
Stress Models

Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms.

scholarly journals eEF1A2 controls local translation and actin dynamics in structural synaptic plasticity

2020 ◽  
Author(s):  
Mònica B. Mendoza ◽  
Sara Gutierrez ◽  
Raúl Ortiz ◽  
David F. Moreno ◽  
Maria Dermit ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Metabotropic Glutamate Receptor ◽  
Elongation Factor ◽  
Structural Plasticity ◽  
Actin Dynamics ◽  
Dependent Manner ◽  
Local Translation ◽  
Translation Elongation Factor ◽  
Translation Elongation

AbstractSynaptic plasticity involves structural modifications in dendritic spines. Increasing evidence suggests that structural plasticity is modulated by local protein synthesis and actin remodeling in a synapsis-specific manner. However, the precise molecular mechanisms connecting synaptic stimulation to these processes in dendritic spines are still unclear. In the present study, we demonstrate that the configuration of phosphorylation sites in eEF1A2, an essential translation elongation factor in neurons, is a key modulator of structural plasticity in dendritic spines. A mutant that cannot be phosphorylated stimulates translation but reduces actin dynamics and spine density. By contrast, the phosphomimetic variant loosens its association with F-actin and becomes inactive as a translation elongation factor. Metabotropic glutamate receptor signaling triggers a transient dissociation of eEF1A2 from its GEF protein in dendritic spines, in a phospho-dependent manner. We propose that eEF1A2 establishes a crosstalk mechanism that coordinates local translation and actin dynamics during spine remodeling.

scholarly journals FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits

2019 ◽  
Vol 28 (22) ◽  
pp. 3777-3791 ◽  
Author(s):  
Wan Yun Ho ◽  
Jer-Cherng Chang ◽  
Sheue-Houy Tyan ◽  
Yi-Chun Yen ◽  
Kenneth Lim ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Dependent Manner ◽  
Spine Density ◽  
Preferential Expression ◽  
Fused In Sarcoma ◽  
Endogenous Expression ◽  
Term Potentiation ◽  
The Central Nervous System

Abstract Pathological fused in sarcoma (FUS) inclusions are found in 10% of patients with frontotemporal dementia and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations. Current work indicates that FUS mutations may incur gain-of-toxic functions to drive ALS pathogenesis. However, how FUS dysfunction may affect cognition remains elusive. Using a mouse model expressing wild-type human FUS mimicking the endogenous expression pattern and level within the central nervous system, we found that they developed hippocampus-mediated cognitive deficits accompanied by an age-dependent reduction in spine density and long-term potentiation in their hippocampus. However, there were no apparent FUS aggregates, nuclear envelope defects and cytosolic FUS accumulation. These suggest that these proposed pathogenic mechanisms may not be the underlying causes for the observed cognitive deficits. Unbiased transcriptomic analysis identified expression changes in a small set of genes with preferential expression in the neurons and oligodendrocyte lineage cells. Of these, we focused on Sema5a, a gene involved in axon guidance, spine dynamics, Parkinson’s disease and autism spectrum disorders. Critically, FUS binds directly to Sema5a mRNA and regulates Sema5a expression in a FUS-dose-dependent manner. Taken together, our data suggest that FUS-driven Sema5a deregulation may underlie the cognitive deficits in FUS transgenic mice.

scholarly journals Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex

2021 ◽  
Vol 22 (24) ◽  
pp. 13201
Author(s):  
Songphon Kanlayaprasit ◽  
Surangrat Thongkorn ◽  
Pawinee Panjabud ◽  
Depicha Jindatip ◽  
Valerie W. Hu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Prefrontal Cortex ◽  
Bisphenol A ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Postmortem Brain ◽  
Dependent Manner ◽  
Distribution Analysis ◽  
Docking Analysis ◽  
Specific Effects

Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome–interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring’s prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring’s prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.

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 ◽  
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 Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Xiaona Wang ◽  
Chao Gao ◽  
Yaodong Zhang ◽  
Shunan Hu ◽  
Yidan Qiao ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Action Potential ◽  
Glutamate Receptor ◽  
Neuronal Excitability ◽  
Metabotropic Glutamate Receptor ◽  
Lentiviral Vector ◽  
Scientific Basis ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests

Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.

scholarly journals Pro-inflammatory cytokine polymorphisms and interactions with dietary alcohol and estrogen, risk factors for invasive breast cancer using a post genome-wide analysis for gene–gene and gene–lifestyle interaction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Su Yon Jung ◽  
Jeanette C. Papp ◽  
Eric M. Sobel ◽  
Matteo Pellegrini ◽  
Herbert Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Visceral Obesity ◽  
Cumulative Exposure ◽  
Environment Interaction ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Reduction Methods

AbstractMolecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized. In this study, we explored the role of pro-inflammatory cytokines such as C-reactive protein (CRP) and interleukin-6 (IL-6) in those pathways at the genome-wide level. With single-nucleotide polymorphisms (SNPs) in the biomarkers and lifestyles together, we further constructed risk profiles to improve predictability for breast cancer. Our earlier genome-wide association gene-environment interaction study used large cohort data from the Women’s Health Initiative Database for Genotypes and Phenotypes Study and identified 88 SNPs associated with CRP and IL-6. For this study, we added an additional 68 SNPs from previous GWA studies, and together with 48 selected lifestyles, evaluated for the association with breast cancer risk via a 2-stage multimodal random survival forest and generalized multifactor dimensionality reduction methods. Overall and in obesity strata (by body mass index, waist, waist-to-hip ratio, exercise, and dietary fat intake), we identified the most predictive genetic and lifestyle variables. Two SNPs (SALL1 rs10521222 and HLA-DQA1 rs9271608) and lifestyles, including alcohol intake, lifetime cumulative exposure to estrogen, and overall and visceral obesity, are the most common and strongest predictive markers for breast cancer across the analyses. The risk profile that combined those variables presented their synergistic effect on the increased breast cancer risk in a gene–lifestyle dose-dependent manner. Our study may contribute to improved predictability for breast cancer and suggest potential interventions for the women with the risk genotypes and lifestyles to reduce their breast cancer risk.

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