scholarly journals Aberrant Mitochondrial Morphology and Function in the BTBR Mouse Model of Autism Is Improved by Two Weeks of Ketogenic Diet

2020 ◽  
Vol 21 (9) ◽  
pp. 3266 ◽  
Author(s):  
Younghee Ahn ◽  
Rasha Sabouny ◽  
Bianca R. Villa ◽  
Nellie C. Yee ◽  
Richelle Mychasiuk ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ketogenic Diet ◽  
Mitochondrial Function ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Mitochondrial Morphology ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Fragmentation ◽  
Low Carbohydrate Diet ◽  
Btbr Mouse

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that exhibits a common set of behavioral and cognitive impairments. Although the etiology of ASD remains unclear, mitochondrial dysfunction has recently emerged as a possible causative factor underlying ASD. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that augments mitochondrial function, and has been shown to reduce autistic behaviors in both humans and in rodent models of ASD. The aim of the current study was to examine mitochondrial bioenergetics in the BTBR mouse model of ASD and to determine whether the KD improves mitochondrial function. We also investigated changes in mitochondrial morphology, which can directly influence mitochondrial function. We found that BTBR mice had altered mitochondrial function and exhibited smaller more fragmented mitochondria compared to C57BL/6J controls, and that supplementation with the KD improved both mitochondrial function and morphology. We also identified activating phosphorylation of two fission proteins, pDRP1S616 and pMFFS146, in BTBR mice, consistent with the increased mitochondrial fragmentation that we observed. Intriguingly, we found that the KD decreased pDRP1S616 levels in BTBR mice, likely contributing to the restoration of mitochondrial morphology. Overall, these data suggest that impaired mitochondrial bioenergetics and mitochondrial fragmentation may contribute to the etiology of ASD and that these alterations can be reversed with KD treatment.

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 Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Lorena Coretti ◽  
Claudia Cristiano ◽  
Ermanno Florio ◽  
Giovanni Scala ◽  
Adriano Lama ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Microbiota Composition ◽  
Btbr Mouse ◽  
Gut Microbiota Composition

scholarly journals Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Richard E. Frye ◽  
Loïc Lionnard ◽  
Indrapal Singh ◽  
Mohammad A. Karim ◽  
Hanane Chajra ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Complex I ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Mitochondrial Metabolism ◽  
Spectrum Disorder ◽  
Mitochondrial Morphology ◽  
Complex Iv ◽  
Children With Asd

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.

scholarly journals A Ketogenic Diet and the Treatment of Autism Spectrum Disorder

2021 ◽  
Vol 9 ◽  
Author(s):  
Qinrui Li ◽  
Jingjing Liang ◽  
Na Fu ◽  
Ying Han ◽  
Jiong Qin
Keyword(s):  
Autism Spectrum Disorder ◽  
Ketogenic Diet ◽  
Mammalian Target Of Rapamycin ◽  
Stereotyped Behavior ◽  
Autism Spectrum ◽  
The Body ◽  
Spectrum Disorder ◽  
Brain Diseases ◽  
Low Carbohydrate Diet ◽  
Underlying Mechanisms

Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interaction. There are no curative treatments for children with ASD. The ketogenic diet (KD) is a high-fat, appropriate-protein, and low-carbohydrate diet that mimics the fasting state of the body and is proven beneficial in drug-resistant epilepsy and some other brain diseases. An increasing number of studies demonstrated that a KD improved autistic behavior, but the underlying mechanisms are not known. We reviewed the neuroprotective role of a KD in ASD, which is likely mediated via improvements in energy metabolism, reductions in antioxidative stress levels, control of neurotransmitters, inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, and modulation of the gut microbiota. A KD is likely a safe and effective treatment for ASD.

Differential Expression of Hippocampal Circular RNAs in the BTBR Mouse Model for Autism Spectrum Disorder

2020 ◽  
Vol 57 (5) ◽  
pp. 2301-2313 ◽  
Author(s):  
Silvia Gasparini ◽  
Giorgia Del Vecchio ◽  
Silvia Gioiosa ◽  
Tiziano Flati ◽  
Tiziana Castrignano ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Differential Expression ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Circular Rnas ◽  
Btbr Mouse

scholarly journals The effects of aging on the BTBR mouse model of autism spectrum disorder

2014 ◽  
Vol 6 ◽  
Author(s):  
Joan M. Jasien ◽  
Caitlin M. Daimon ◽  
Rui Wang ◽  
Bruce K. Shapiro ◽  
Bronwen Martin ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Btbr Mouse ◽  
Effects Of Aging

scholarly journals Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder

2015 ◽  
Vol 6 ◽  
Author(s):  
Caitlin M. Daimon ◽  
Joan M. Jasien ◽  
William H. Wood ◽  
Yongqing Zhang ◽  
Kevin G. Becker ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Btbr Mouse

scholarly journals Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

2020 ◽  
Author(s):  
Aya Osman ◽  
Nicholas L. Mervosh ◽  
Ana N. Strat ◽  
Katherine R. Meckel ◽  
Tanner J. Euston ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Environmental Factors ◽  
Mouse Model ◽  
Translational Research ◽  
Gut Microbiome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Research Strategies ◽  
Stage Of Development

AbstractAutism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3KO mice. Additionally, we found that Shank3KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.

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.

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