scholarly journals Translational animal models of autism and neurodevelopmental disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 293-305 ◽  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Homologous Genes ◽  
Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

2021 ◽  
Author(s):  
Kan Yang ◽  
Yuhan Shi ◽  
Xiujuan Du ◽  
Yuefang Zhang ◽  
Shifang Shan ◽  
...  
Keyword(s):  
Social Interaction ◽  
De Novo ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genetic Components ◽  
Truncating Mutation ◽  
Synaptic Functions ◽  
Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

scholarly journals Linking Autism Risk Genes to Disruption of Cortical Development

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2500
Author(s):  
Marta Garcia-Forn ◽  
Andrea Boitnott ◽  
Zeynep Akpinar ◽  
Silvia De Rubeis
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Cortical Development ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genome Wide Association Studies ◽  
Restricted Interests ◽  
Risk Genes ◽  
Whole Exome

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.

Elucidation of Abnormal Extracellular Regulated Kinase (ERK) Signaling and Associations with Syndromic and Non-syndromic Autism

2020 ◽  
Vol 21 ◽  
Author(s):  
Aarti Tiwari ◽  
Saloni Rahi ◽  
Sidharth Mehan
Keyword(s):  
Autism Spectrum Disorder ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Erk Signaling ◽  
Erk Pathway ◽  
Signaling Mechanism ◽  
Syndromic Autism

Abstract: Autism is a highly inherited and extremely complex disorder in which results from various cases indicate chro-mosome anomalies, unusual single-gene mutations, and multiplicative effects of particular gene variants, characterized pri-marily by impaired speech and social interaction and restricted behavior. The precise etiology of Autism Spectrum Disorder (ASD) is currently unclear. The extracellular signal-regulated kinase (ERK) signaling mechanism affects neurogenesis and neuronal plasticity during the development of the central nervous mechanism. In this regard, the pathway of ERK has re-cently gained significant interest in the pathogenesis of ASD. The mutation occurs in a few ERK components. Besides, the ERK pathway dysfunction lies in the upstream of modified translation and contributes to synapse pathology in syndromic types of autism. In this review, we highlight the ERK pathway as a target for neurodevelopmental disorder autism. In addi-tion, we summarize the regulation of the ERK pathway with ERK inhibitors in neurological disorders. In conclusion, a better understanding of the ERK signaling pathway provides a range of therapeutic options for autism spectrum disorder

scholarly journals Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B

2020 ◽  
Author(s):  
Nisim Perets ◽  
Oded Oron ◽  
Shay Herman ◽  
Evan Elliott ◽  
Daniel Offen
Keyword(s):  
Mouse Model ◽  
Social Communication ◽  
Neurodevelopmental Disorder ◽  
Genetic Mutation ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Mice Model ◽  
Restricted Interests ◽  
The Social ◽  
Core Symptoms

Abstract Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with main core symptoms including deficits in social-communication abilities and repetitive behaviors/restricted interests. ASD affects 1 of 88 children worldwide and currently there is no sufficiently effective treatment that alleviates its core deficits. In our previous studies, we have shown that both MSC and MSC-exo can ameliorate core ASD-like symptoms of the BTBR multifactorial mouse model of autism. Furthermore, we have demonstrated that the MSC-exo migrate to distinct neuropathological areas in several mouse models, including the frontal cortex and cerebellum in BTBR mice. In contrast to BTBR mice, which is a multifactorial model of autism, the Shank3B KO mouse is used to study ASD which develops due to a specific genetic mutation. Here we demonstrate that intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization and reduces repetitive behaviors. We also observed an increase of GABRB1 in the prefrontal cortex. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of in this mouse model autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.

The Well-Being of Families living with Autism Spectrum Disorder in Qatar

2019 ◽  
Author(s):  
Naomi V. Ekas ◽  
◽  
Abdallah M. Badahdah ◽  
Azza O. Abdelmoneium
Keyword(s):  
Neurodevelopmental Disorder ◽  
Children With Autism ◽  
Well Being ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Psychological Well Being ◽  
Social And Emotional ◽  
Raising Awareness ◽  
The Government

Autism is a lifelong neurodevelopmental disorder that affects approximately 1% of children worldwide. Children with autism have difficulties in social interactions and communication and often engage in repetitive behaviors or have restricted interests (American Psychiatric Association, 2013). As a result of their child’s autism diagnosis, parents of children with autism often experience increased stress and poorer psychological well-being. Moreover, relationships within the family (e.g., marital relationship) may be negatively impacted. Addressing the needs of family members, particularly parents, is critical, as decades of research have shown that parents’ psychological well-being can affect the way that parents interact with their children. These interactional patterns can, in turn, impact children’s development in many of the areas that are affected by autism, including the social and emotional, language, and cognitive domains. The government of Qatar has recently taken steps to address the needs of children with autism and their families. The overarching aim of the Qatar National Autism Plan is to improve the lives of individuals with autism and their families. The six pillars of the National Autism Plan are designed to address the needs of individuals with autism and their families in areas such as raising awareness about autism, receiving early diagnosis, and accessing treatment and education. Once these needs are met, it is likely that the families of children with autism in Qatar can flourish. However, there are likely to be other challenges and unmet needs that the National Autism Plan does not address, and it was with this in mind that this first comprehensive study of families of children with autism in Qatar was undertaken.

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization

2015 ◽  
Vol 396 (11) ◽  
pp. 1233-1240 ◽  
Author(s):  
Lucia Ciccoli ◽  
Claudio De Felice ◽  
Silvia Leoncini ◽  
Cinzia Signorini ◽  
Alessio Cortelazzo ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Morphological Changes ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Current Evidence ◽  
Loss Of Function ◽  
Beneficial Effects ◽  
Spectrum Disorders

Abstract In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a ‘model’ condition for autism spectrum disorders.

scholarly journals fMRI activation during a language task in adolescents with ASD

2008 ◽  
Vol 14 (6) ◽  
pp. 967-979 ◽  
Author(s):  
TRACEY A. KNAUS ◽  
ANDREW M. SILVER ◽  
KRISTEN A. LINDGREN ◽  
NOUCHINE HADJIKHANI ◽  
HELEN TAGER-FLUSBERG
Keyword(s):  
Semantic Processing ◽  
Neurodevelopmental Disorder ◽  
Naming Task ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Control Group ◽  
Typically Developing ◽  
Restricted Interests ◽  
Or Efficiency ◽  
Adolescents With Asd

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by language and communication impairments, social impairments, and repetitive behaviors or restricted interests. Previous studies of semantic functions have found differences in semantic processing and differences in the activation of the language network in adults with ASD compared to controls. The goal of this study is to examine semantic functions in adolescents with ASD compared to typically developing adolescents. We utilized fMRI with a reading version of a response-naming task to investigate activation in 12 right-handed adolescent boys with ASD and 12 typically developing boys. Both groups performed the task at ceiling levels. Boys with ASD had significantly stronger activation than controls in Broca's area, which was less left lateralized in ASD individuals. Controls had a significant correlation between frontal and temporal language area activation in the left hemisphere, whereas ASD adolescents did not. Direct group comparisons revealed additional regions activated in the ASD group relative to the control group. These results suggest differences in semantic organization, approaches to the semantic task, or efficiency in semantic processing in ASD adolescents relative to typically developing adolescents. (JINS, 2008,14, 967–979.)

scholarly journals Biological implications of genetic variations in autism spectrum disorders from genomics studies

2021 ◽  
Author(s):  
Yue Zhang ◽  
Xuanshi Liu ◽  
Ruolan Guo ◽  
Wenjian Xu ◽  
Qi Guo ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Current Evidence ◽  
Restricted Interests ◽  
Coding Regions ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) is a highly heterogeneous neurodevelopmental condition characterized by atypical social interaction and communication together with repetitive behaviors and restricted interests. The prevalence of ASD has been increased these years. Compelling evidence has shown that genetic factors contribute largely to the development of ASD. However, knowledge about its genetic etiology and pathogenesis is limited. Broad applications of genomics studies have revealed the importance of gene mutations at protein-coding regions as well as the interrupted non-coding regions in the development of ASD. In this review, we summarize the current evidence for the known molecular genetic basis and possible pathological mechanisms as well as the risk genes and loci of ASD. Functional studies for the underlying mechanisms are also implicated. The understanding of the genetics and genomics of ASD is important for the genetic diagnosis and intervention for this condition.

scholarly journals Leveraging video data from a digital smartphone autism therapy to train an emotion detection classifier

2021 ◽  
Author(s):  
Cathy Hou ◽  
Haik Kalantarian ◽  
Peter Washington ◽  
Kaiti Dunlap ◽  
Dennis P. Wall
Keyword(s):  
Emotion Recognition ◽  
Neurodevelopmental Disorder ◽  
The United States ◽  
Autism Spectrum ◽  
Video Data ◽  
Repetitive Behaviors ◽  
Mobile Systems ◽  
Superior Performance ◽  
Restricted Interests ◽  
Autism Therapy

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting one in 40 children in the United States and is associated with impaired social interactions, restricted interests, and repetitive behaviors. Previous studies have demonstrated the promise of applying mobile systems with real-time emotion recognition to autism therapy, but existing platforms have shown limited performance on videos of children with ASD. We propose the development of a new emotion classifier designed specifically for pediatric populations, trained with images crowdsourced from an educational mobile charades-style game: Guess What?. We crowdsourced the acquisition of videos of children portraying emotions during remote game sessions of Guess What? that yielded 6,344 frames from fifteen subjects. Two raters manually labeled the frames with four of the Ekman universal emotions (happy, scared, angry, sad), a neutral class, and n/a for frames with an indeterminable label. The data were pre-processed, and a model was trained with a transfer-learning and neural-architecture-search approach using the Google Cloud AutoML Vision API. The resulting classifier was evaluated against existing approaches (Azure Face API from Microsoft and Rekognition from Amazon Web Services) using the standard metrics of F1 score. The resulting classifier demonstrated superior performance across all evaluated emotions, supporting our hypothesis that a model trained with a pediatric dataset would outperform existing emotion-recognition approaches for the population of interest. These results suggest a new strategy to develop precision therapy for autism at home by integrating the model trained with a personalized dataset to the mobile game.

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