Genetic modifications associated with ketogenic diet treatment in the BTBR<sup>T+Tf/J</sup> mouse model of autism spectrum disorder

Mychasiuk, Richelle; Rho, Jong M.

doi:10.1002/aur.1682

Cited by 37 publications

(20 citation statements)

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“…The mice were born and reared in a quiet, temperature-controlled room and entrained to a 12-hour light-dark cycle. After weaning at postnatal day 21 (PD21), the mice were placed on either standard diet (SD) or ketogenic diet (KD; 6.3:1 ratio by weight of fat to carbohydrate plus protein; Bio-Serv F3666, Frenchtown, NJ, USA) for 10-14 days [73,74] based on our previous experiments [38,45]. F3666 is a ketogenic chow composed of lard, butter, corn oil, casein, cellulose, mineral mix, vitamin mix, and dextrose.…”

Section: Animals and Dietary Proceduresmentioning

confidence: 99%

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

Ahn

Sabouny

Villa

et al. 2020

IJMS

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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.

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Section: Animals and Dietary Proceduresmentioning

confidence: 99%

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

Ahn

Sabouny

Villa

et al. 2020

IJMS

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“…To examine the underlying mechanism of the abnormal cerebellar development and connection formation in BTBR mice, we performed RNA-Seq in whole cerebella tissue of WT and BTBR mice at postnatal day 14. Previous studies were performed in other brain regions of BTBR mice vs WT mice (35)(36)(37), but few studies were done in cerebella. We identified 3992 differentially expressed genes (P<0.05), with 1858 upregulated and 2134 downregulated (Fig.6 A) (Fig.s4), the critical genes were identified, and significantly increased TRPC6 was a highly suspicious candidate in BTBR mice (Fig.6 C).…”

Section: Dysregulated Trpc Genes Impaired Cerebellar Development In Bmentioning

confidence: 99%

Abnormal cerebellar development is involved in dystonia-like behaviors and motor dysfunction of autistic BTBR mice

Xiao

Zhong

et al. 2019

Preprint

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Background: Motor control and learning impairments are common complications in autistic individuals. Abnormal cerebellar development during critical phases may disrupt these motor functions and lead to the development of autistic motor dysfunction. However, the underlying mechanisms behind these impairments are not clear.Methods: Dystonic behavior was elicited using tail suspension. Motor control and learning were detected by means of the grid hang test, ladder rung walking, accelerating rotarod, and open field locomotion. Cerebellar development was morphometrically and histologically detected during critical phases. RNA sequencing was used to compare differential gene expression to provide an in-depth interpretation of molecular mechanisms.Results: BTBR mice, as a model of autism, exhibited severe dystonic behavior and motor coordination or motor learning impairments. The onset of these abnormal movements coincided with the increased proliferation of granule neurons and enhanced foliation, and Purkinje cells exhibited morphological hypotrophy with increased dendritic spine formation but suppressed maturation. The migration of granule neurons seemed unaffected. Transcriptional analyses confirmed the differential expression of genes involved in abnormal neurogenesis and revealed TRPC6 as a critical regulator in proliferation and synaptic formation. Conclusion:These findings indicate that abnormal cerebellar development is closely related to dystonia and motor dysfunction of BTBR mice and that TRPC6 may be a novel risk gene for ASD that may participate in the pathological process of autistic movement disorders.

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“…BTBR mice display deficits in social interaction and communication assays and exhibit repetitive and stereotyped behaviors. During the relatively short time since its discovery as an ASD model, the BTBR strain has been increasingly used to study the etiology and to uncover potential interventions for ASD (Moy et al, 2007 ; McFarlane et al, 2008 ; Llaneza et al, 2010 ; Ruskin et al, 2013 ; Cheng et al, 2016 ; Mychasiuk and Rho, 2016 ; Newell et al, 2016 ). Ruskin and colleagues reported that the BTBR mice showed decreased sociability in the three-chamber test, decreased self-directed repetitive behavior, and improved social communication in a food preference assay after being fed a KD (Ruskin et al, 2013 ).…”

Section: Metabolic Therapy and Asd—evidence From Animal Modelsmentioning

confidence: 99%

Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches

Cheng

Rho

Masino

2017

Front. Mol. Neurosci.

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Autism spectrum disorder (ASD) is characterized by deficits in sociability and communication, and increased repetitive and/or restrictive behaviors. While the etio-pathogenesis of ASD is unknown, clinical manifestations are diverse and many possible genetic and environmental factors have been implicated. As such, it has been a great challenge to identify key neurobiological mechanisms and to develop effective treatments. Current therapies focus on co-morbid conditions (such as epileptic seizures and sleep disturbances) and there is no cure for the core symptoms. Recent studies have increasingly implicated mitochondrial dysfunction in ASD. The fact that mitochondria are an integral part of diverse cellular functions and are susceptible to many insults could explain how a wide range of factors can contribute to a consistent behavioral phenotype in ASD. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), used for nearly a century to treat medically intractable epilepsy, has been shown to enhance mitochondrial function through a multiplicity of mechanisms and affect additional molecular targets that may address symptoms and comorbidities of ASD. Here, we review the evidence for the use of metabolism-based therapies such as the KD in the treatment of ASD as well as emerging co-morbid models of epilepsy and autism. Future research directions aimed at validating such therapeutic approaches and identifying additional and novel mechanistic targets are also discussed.

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Genetic modifications associated with ketogenic diet treatment in the BTBR^T+Tf/J mouse model of autism spectrum disorder

Cited by 37 publications

References 69 publications

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

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

Abnormal cerebellar development is involved in dystonia-like behaviors and motor dysfunction of autistic BTBR mice

Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches

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Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder

Cited by 37 publications

References 69 publications

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

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

Abnormal cerebellar development is involved in dystonia-like behaviors and motor dysfunction of autistic BTBR mice

Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches

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Genetic modifications associated with ketogenic diet treatment in the BTBR^T+Tf/J mouse model of autism spectrum disorder