scholarly journals Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Bianca De Filippis ◽  
Mattia Musto ◽  
Luisa Altabella ◽  
Emilia Romano ◽  
Rossella Canese ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Motor Coordination ◽  
Neurodevelopmental Disorder ◽  
Fine Motor ◽  
Resonance Spectroscopy ◽  
Fine Motor Skill ◽  
Female Mice ◽  
Fine Grain ◽  
Motor Abnormalities

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by thein vivomagnetic resonance spectroscopy (MRS) analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age) were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag testandCapellini handling task). A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.

CheerBrush: A Novel Interactive Augmented Reality Coaching System for Toothbrushing Skills in Children with Autism Spectrum Disorder

2021 ◽  
Vol 14 (4) ◽  
pp. 1-20
Author(s):  
Z. Kevin Zheng ◽  
Nandan Sarkar ◽  
Amy Swanson ◽  
Amy Weitlauf ◽  
Zachary Warren ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Augmented Reality ◽  
Neurodevelopmental Disorder ◽  
The United States ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Fine Motor ◽  
Fine Motor Skill ◽  
Intelligent Support ◽  
Children With Asd

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder that impacts one in every 54 children in the United States. Some children with ASD have learning and fine motor skill challenges that contribute to difficulties completing daily living tasks such as toothbrushing. Lack of toothbrushing skills may cause increased need for dental care and negative social feedback from peers. Technology based intelligent support systems offer the advantages of being accessible, engaging, and cost-effective. In this work, we present a novel interactive augmented reality coaching system, CheerBrush, to improve the toothbrushing skills of children with ASD. CheerBrush allows children to manipulate virtual objects like a toothbrush and toothpaste with their actual hand motions to practice the steps of toothbrushing. The virtual tasks of CheerBrush demonstrate these steps using audio and visual cues, while also showing the brushing process through a virtual avatar. CheerBrush also assesses toothbrushing skills with a custom designed mechatronic toothbrush to evaluate the system's coaching effectiveness. A feasibility study with 12 children (six children with ASD and six typically developing children) was conducted to evaluate the acceptability and effectiveness of CheerBrush. The data showed improvements in the toothbrushing motions and reduced stress for the children in the post-test. CheerBrush detects real-time movement of children and interacts with them by augmented reality, feedback and multimodal hints. We believe that CheerBrush has the potential to provide a low-cost, engaging and, beneficial intelligent support system to improve the toothbrushing skills of children with ASD.

scholarly journals Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital

2015 ◽  
Vol 12 (2) ◽  
pp. 477-490 ◽  
Author(s):  
Dongliang Ma ◽  
Su-In Yoon ◽  
Chih-Hao Yang ◽  
Guillaume Marcy ◽  
Na Zhao ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Hippocampal Neurons ◽  
Granule Cells ◽  
Binding Protein ◽  
Neurodevelopmental Disorder ◽  
Network Activity ◽  
Aminobutyric Acid ◽  
Structural Defects

Abstract Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.

scholarly journals Brain-Derived Neurotrophic Factor Secreting Human Mesenchymal Stem Cells Improve Outcomes in Rett Syndrome Mouse Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Hyo Jeong Kim ◽  
Delger Bayarsaikhan ◽  
Jaesuk Lee ◽  
Govigerel Bayarsaikhan ◽  
Bonghee Lee
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Rett Syndrome ◽  
Neurotrophic Factor ◽  
Neurodevelopmental Disorder ◽  
Neuronal Cell ◽  
Brain Derived Neurotrophic Factor ◽  
The Body ◽  
Human Umbilical Cord

Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene; MeCP2 regulates the expression of brain-derived neurotrophic factor (BDNF) and increasing BDNF levels ameliorates RTT symptoms. However, the clinical application of BDNF is limited, because of its short half-life and low penetrance across the blood-brain barrier. In this study, we generated BDNF-secreting mesenchymal stem cells (MSCs) from the human umbilical cord cells, using CRISPR-Cas9. We studied the effects of BDNF-MSCs in MECP2 knockout and MECP2-deficient mice. BDNF-MSCs upregulated the expression of BDNF, pAKT, and pERK1/2 and downregulated that of pp38, both in vitro and in vivo. In our in vivo experiments, BDNF-MSCs increased the body and brain weights in mice. BDNF-MSCs increased the neuronal cell numbers in the hippocampus, cortex, and striatum; in addition, they increased the number of synapses. BDNF-MSCs upregulated BDNF and the activity of BDNF downstream effectors, such as pAKT and pERK 1/2; this upregulation was persistent. In conclusion, BDNF-MSCs generated using CRISPR-Cas9 could be a therapeutic strategy for treating RTT.

scholarly journals JNK signaling provides a novel therapeutic target for Rett syndrome

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Clara Alice Musi ◽  
Anna Maria Castaldo ◽  
Anna Elisa Valsecchi ◽  
Sara Cimini ◽  
Noemi Morello ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Clinical Symptoms ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Jnk Signaling ◽  
Functional Changes ◽  
Jnk Activation ◽  
Stress Pathway

Abstract Background Rett syndrome (RTT) is a monogenic X-linked neurodevelopmental disorder characterized by loss-of-function mutations in the MECP2 gene, which lead to structural and functional changes in synapse communication, and impairments of neural activity at the basis of cognitive deficits that progress from an early age. While the restoration of MECP2 in animal models has been shown to rescue some RTT symptoms, gene therapy intervention presents potential side effects, and with gene- and RNA-editing approaches still far from clinical application, strategies focusing on signaling pathways downstream of MeCP2 may provide alternatives for the development of more effective therapies in vivo. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) stress pathway in the pathogenesis of RTT using different animal and cell models and evaluate JNK inhibition as a potential therapeutic approach. Results We discovered that the c-Jun N-terminal kinase (JNK) stress pathway is activated in Mecp2-knockout, Mecp2-heterozygous mice, and in human MECP2-mutated iPSC neurons. The specific JNK inhibitor, D-JNKI1, promotes recovery of body weight and locomotor impairments in two mouse models of RTT and rescues their dendritic spine alterations. Mecp2-knockout presents intermittent crises of apnea/hypopnea, one of the most invalidating RTT pathological symptoms, and D-JNKI1 powerfully reduces this breathing dysfunction. Importantly, we discovered that also neurons derived from hiPSC-MECP2 mut show JNK activation, high-phosphorylated c-Jun levels, and cell death, which is not observed in the isogenic control wt allele hiPSCs. Treatment with D-JNKI1 inhibits neuronal death induced by MECP2 mutation in hiPSCs mut neurons. Conclusions As a summary, we found altered JNK signaling in models of RTT and suggest that D-JNKI1 treatment prevents clinical symptoms, with coherent results at the cellular, molecular, and functional levels. This is the first proof of concept that JNK plays a key role in RTT and its specific inhibition offers a new and potential therapeutic tool to tackle RTT.

scholarly journals Mathematical Skills in 3- and 5-Year-Olds with Spina Bifida and Their Typically Developing Peers: A Longitudinal Approach

2011 ◽  
Vol 17 (3) ◽  
pp. 431-444 ◽  
Author(s):  
Marcia A. Barnes ◽  
Allison Stubbs ◽  
Kimberly P. Raghubar ◽  
Alba Agostino ◽  
Heather Taylor ◽  
...  
Keyword(s):  
Spina Bifida ◽  
Motor Skill ◽  
Neurodevelopmental Disorder ◽  
Vocabulary Knowledge ◽  
Fine Motor ◽  
Typically Developing ◽  
Fine Motor Skill ◽  
Motor Abilities ◽  
Visual Spatial ◽  
Object Based

AbstractPreschoolers with spina bifida (SB) were compared to typically developing (TD) children on tasks tapping mathematical knowledge at 36 months (n = 102) and 60 months of age (n = 98). The group with SB had difficulty compared to TD peers on all mathematical tasks except for transformation on quantities in the subitizable range. At 36 months, vocabulary knowledge, visual–spatial, and fine motor abilities predicted achievement on a measure of informal math knowledge in both groups. At 60 months of age, phonological awareness, visual–spatial ability, and fine motor skill were uniquely and differentially related to counting knowledge, oral counting, object-based arithmetic skills, and quantitative concepts. Importantly, the patterns of association between these predictors and mathematical performance were similar across the groups. A novel finding is that fine motor skill uniquely predicted object-based arithmetic abilities in both groups, suggesting developmental continuity in the neurocognitive correlates of early object-based and later symbolic arithmetic problem solving. Models combining 36-month mathematical ability and these language-based, visual–spatial, and fine motor abilities at 60 months accounted for considerable variance on 60-month informal mathematical outcomes. Results are discussed with reference to models of mathematical development and early identification of risk in preschoolers with neurodevelopmental disorder. (JINS, 2011, 17, 431–444)

scholarly journals Antiglycative Activity and RAGE Expression in Rett Syndrome

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 161 ◽  
Author(s):  
Valeria Cordone ◽  
Alessandra Pecorelli ◽  
Mascia Benedusi ◽  
Silvano Santini ◽  
Stefano Falone ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurological Diseases ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
Cellular Stress Response ◽  
Defense Systems ◽  
Inflammatory Status ◽  
Glycation End Products ◽  
Rage Expression

Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status (OxInflammation). Methylglyoxal (MG), a glycolytic by-product with cytotoxic and pro-oxidant power, is the major precursor in vivo of advanced glycation end products (AGEs), which are known to exert their detrimental effect via receptor- (e.g., RAGE) or non-receptor-mediated mechanisms in several neurological diseases. On this basis, we aimed to compare fibroblasts from healthy subjects (CTR) with fibroblasts from RTT patients (N = 6 per group), by evaluating gene/protein expression patterns, and enzymatic activities of glyoxalases (GLOs), along with the levels of MG-dependent damage in both basal and MG-challenged conditions. Our results revealed that RTT is linked to an alteration of the GLOs system (specifically, increased GLO2 activity), that ensures unchanged MG-dependent damage levels. However, RTT cells underwent more pronounced cell death upon exogenous MG-treatment, as compared to CTR, and displayed lower RAGE levels than CTR, with no alterations following MG-treatment, thus suggesting that an adaptive response to dicarbonyl stress may occur. In conclusion, besides OxInflammation, RTT is associated with reshaping of the major defense systems against dicarbonyl stress, along with an altered cellular stress response towards pro-glycating insults.

scholarly journals MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome

2015 ◽  
Vol 112 (17) ◽  
pp. 5509-5514 ◽  
Author(s):  
Lin Chen ◽  
Kaifu Chen ◽  
Laura A. Lavery ◽  
Steven Andrew Baker ◽  
Chad A. Shaw ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Rett Syndrome ◽  
Dna Sequences ◽  
Neurodevelopmental Disorder ◽  
Adult Brain ◽  
Gene Encoding ◽  
Dna Elements ◽  
Timing Of Onset

Epigenetic mechanisms, such as DNA methylation, regulate transcriptional programs to afford the genome flexibility in responding to developmental and environmental cues in health and disease. A prime example involving epigenetic dysfunction is the postnatal neurodevelopmental disorder Rett syndrome (RTT), which is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 regulates transcription or why RTT features appear 6–18 months after birth. Here we report integrated analyses of genomic binding of MeCP2, gene-expression data, and patterns of DNA methylation. In addition to the expected high-affinity binding to methylated cytosine in the CG context (mCG), we find a distinct epigenetic pattern of substantial MeCP2 binding to methylated cytosine in the non-CG context (mCH, where H = A, C, or T) in the adult brain. Unexpectedly, we discovered that genes that acquire elevated mCH after birth become preferentially misregulated in mouse models of MeCP2 disorders, suggesting that MeCP2 binding at mCH loci is key for regulating neuronal gene expression in vivo. This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level of Bdnf, a gene implicated in the pathophysiology of RTT. This study thus provides insight into the molecular mechanism governing MeCP2 targeting and sheds light on the delayed onset of RTT symptoms.

Spectroscopic imaging of human disease

1996 ◽  
Vol 54 ◽  
pp. 884-885
Author(s):  
D.J. Meyerhoff
Keyword(s):  
Magnetic Field ◽  
Magnetic Resonance ◽  
Field Gradient ◽  
Human Disease ◽  
Morphological Changes ◽  
Magnetic Field Gradient ◽  
Spectroscopic Imaging ◽  
Resonance Spectroscopy ◽  
Tissue Water

Magnetic Resonance Imaging (MRI) observes tissue water in the presence of a magnetic field gradient to study morphological changes such as tissue volume loss and signal hyperintensities in human disease. These changes are mostly non-specific and do not appear to be correlated with the range of severity of a certain disease. In contrast, Magnetic Resonance Spectroscopy (MRS), which measures many different chemicals and tissue metabolites in the millimolar concentration range in the absence of a magnetic field gradient, has been shown to reveal characteristic metabolite patterns which are often correlated with the severity of a disease. In-vivo MRS studies are performed on widely available MRI scanners without any “sample preparation” or invasive procedures and are therefore widely used in clinical research. Hydrogen (H) MRS and MR Spectroscopic Imaging (MRSI, conceptionally a combination of MRI and MRS) measure N-acetylaspartate (a putative marker of neurons), creatine-containing metabolites (involved in energy processes in the cell), choline-containing metabolites (involved in membrane metabolism and, possibly, inflammatory processes),

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