scholarly journals CHD8 regulates gut epithelial cell function and affects autism-related behaviours through the gut-brain axis

2021 ◽  
Author(s):  
Ipsita Chaterjee ◽  
Dmitriy Getselter ◽  
Nasreen Ghaneem ◽  
Shai Bel ◽  
Evan Elliott
Keyword(s):  
Epithelial Cells ◽  
Cell Function ◽  
Neurodevelopmental Disorder ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Direct Role ◽  
Tuft Cells ◽  
Core Symptoms ◽  
The Relationship ◽  
Specific Deletion

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early onset deficits in social behavior and repetitive behavior. Chromodomain helicase DNA binding protein (CHD8) is one of the genes with the strongest association to autism. Alongside with the core symptoms of ASD, individuals with ASD are reported to have gastrointestinal (GI) problems, and a majority of individuals with CHD8 mutations display GI problems. However, the relationship between autism related genes, such as CHD8, gastrointestinal function, and autism related behaviours are yet very unclear. In the current study, we found that mice haploinsufficient for CHD8 have leaky gut, a dysregulated transcriptome in gut epithelial cells, decreased gut tuft cells and goblet cells, and an increase in microbial load. Specific deletion of CHD8 in gut epithelial cells induced an increase in anxiety-related behaviours in, a phenotype that is often observed in autism and full body knockdown of CHD8, in addition to decreased tuft cells. In addition, antibiotic treatment of CHD8 haploinsufficient mice attenuates sociability deficits. Therefore, the current study determines a pathway for autism-related GI deficits, and how these deficits may play a direct role in the development of autism-related behaviours.

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.

Early Life Origins of ASD and ADHD

2021 ◽  
Author(s):  
Yuelong Ji ◽  
Ramkripa Raghavan ◽  
Xiaobin Wang
Keyword(s):  
Risk Factors ◽  
Early Life ◽  
Neurodevelopmental Disorder ◽  
Repetitive Behavior ◽  
Density Lipoprotein ◽  
Cost Effective ◽  
Autism Spectrum ◽  
Male Dominance ◽  
High Rate ◽  
Shared Risk

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication and by the presence of restrictive, repetitive behavior. Attention deficit hyperactivity disorder (ADHD) is another common lifelong neurodevelopmental disorder characterized by three major presentations: predominantly hyperactive/impulsive, predominantly inattentive, and combined. Although ASD and ADHD are different clinical diagnoses, they share various common characteristics, including male dominance, early childhood onset, links to prenatal and perinatal factors, common comorbidity for each other, and, often, persistence into adulthood. They also have both unique and shared risk factors, which originate in early life and have lifelong implications on the affected individuals and families and society. While genetic factors contribute to ASD and ADHD risk, the environmental contribution to ASD and ADHD has been recognized as having potentially equal importance, which raises the hope for early prevention and intervention. Maternal folate levels, maternal metabolic syndrome, and metabolic biomarkers have been associated with the risk of childhood ASD; while maternal high-density lipoprotein, maternal psychosocial stress, and in utero exposure to opioids have been associated with the risk of childhood ADHD. As for shared factors, male sex, preterm birth, placental pathology, and early life exposure to acetaminophen have been associated with both ASD and ADHD. The high rate of comorbidity of ASD and ADHD and their many shared early life risk factors suggest that early identification and intervention of common early life risk factors may be cost-effective to lower the risk of both conditions. Efforts to improve maternal preconception, prenatal, and perinatal health will not only help reduce adverse reproductive and birth outcomes but will also help mitigate the risk of ASD and ADHD associated with those adverse early life events.

Millennium Nutrient N,N-Dimethylglycine (DMG) and its Effectiveness in Autism Spectrum Disorders.

2021 ◽  
Vol 28 ◽  
Author(s):  
Daljeet Singh Dhanjal ◽  
Sonali Bhardwaj ◽  
Chirag Chopra ◽  
Reena Singh ◽  
Jiri Patocka ◽  
...  
Keyword(s):  
Conventional Medicine ◽  
Neurodevelopmental Disorder ◽  
Treatment Options ◽  
Autism Spectrum ◽  
Autistic Children ◽  
Children With Asd ◽  
Drastic Increase ◽  
Spectrum Disorders ◽  
Approved Drugs ◽  
Core Symptoms

: Autism is a neurodevelopmental disorder belonging to the autism spectrum disorder (ASD). In ASDs, the individuals show substantial impairments in social communication, repetitive behaviours, and sensory behaviours deficits in the early stages of their life. Globally, the prevalence of autism is estimated to be less than 1%, especially in high-income countries. In recent decades, there has been a drastic increase in the incidence of ASD, which has put ASD into the category of epidemics. Presently, two US Food and Drug Administration-approved drugs, aripiprazole and risperidone are used to treat symptoms of agitation and irritability in autistic children. However, to date, no medication has been found to treat the core symptoms of ASD. The adverse side effects of conventional medicine and limited treatment options have led families and parents of autistic children to turn to complementary and alternative medicine (CAM) treatments, which are perceived as relatively safe compared to conventional medicine. Recently, N,N-dimethylglycine (DMG), a dietary supplement, has emerged as a useful supplement to improve the mental and physical state of children with ASD. The current review discusses ASD, the prevalence of ASD, CAM approach and efficacy of CAM treatment in children with ASD. Moreover, it highlights the chemistry, pharmacological effect, and clinical studies of DMG, highlighting its potential for improving the lifestyle of children with ASD.

Neurobiology of Autism and Intellectual Disability

2017 ◽  
Author(s):  
Dejan B. Budimirovic ◽  
Megha Subramanian
Keyword(s):  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Full Range ◽  
Therapeutic Targets ◽  
Autism Spectrum ◽  
Fmr1 Gene ◽  
Health Concern ◽  
Complex Disorders ◽  
Mglur5 Antagonist ◽  
Core Symptoms

Fragile X syndrome (FXS) is a neurodevelopmental disorder that manifests with a range of cognitive, behavioral, and social impairments. It is a monogenetic disease caused by silencing of the FMR1 gene, in contrast to autism spectrum disorder (ASD) that is a behaviorally-defined set of complex disorders. Because ASD is a major and growing public health concern, current research is focused on identifying common therapeutic targets among patients with different molecular etiologies. Due to the prevalence of ASD in FXS and its shared neurophysiology with ASD, FXS has been extensively studied as a model for ASD. Studies in the animal models have provided breakthrough insights into the pathophysiology of FXS that have led to novel therapeutic targets for its core deficits (e.g., mGluR theory of fragile X). Yet recent clinical trials of both GABA-B agonist and mGluR5 antagonist revealed a lack of specific and sensitive outcome measures capturing the full range of improvements of patients with FXS. Recent research shows promise for the mapping of the multitude of genetic variants in ASD onto shared pathways with FXS. Nonetheless, in light of the huge level of locus heterogeneity in ASD, further effort in finding convergence in specific molecular pathways and reliable biomarkers is required in order to perform targeted treatment trials with sufficient sample size. This chapter focuses on the neurobehavioral phenotype caused by a full-mutation of the FMR1 gene, namely FXS, and the neurobiology of this disorder of relevance to the targeted molecular treatments of its core symptoms.

scholarly journals Clinical and autoimmune features of a patient with autism spectrum disorder seropositive for anti—NMDA-receptor autoantibody

2017 ◽  
Vol 19 (1) ◽  
pp. 65-70 ◽  
Keyword(s):  
Autism Spectrum Disorder ◽  
Nmda Receptor ◽  
Single Molecule ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Psychotic Symptoms ◽  
Direct Role ◽  
Major Depressive Episodes ◽  
Depressive Episodes

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by dysfunctions in social interactions resulting from a complex interplay between immunogenetic and environmental risk factors. Autoimmunity has been proposed as a major etiological component of ASD. Whether specific autoantibodies directed against brain targets are involved in ASD remains an open question. Here, we identified within a cohort an ASD patient with multiple circulating autoantibodies, including the well-characterized one against glutamate NMDA receptor (NMDAR-Ab). The patient exhibited alexithymia and previously suffered from two major depressive episodes without psychotic symptoms. Using a single molecule-based imaging approach, we demonstrate that neither NMDAR-Ab type G immunoglobulin purified from the ASD patient serum, nor that from a seropositive healthy subject, disorganize membrane NMDAR complexes at synapses. These findings suggest that the autistic patient NMDAR-Abs do not play a direct role in the etiology of ASD and that other autoantibodies directed against neuronal targets should be investigated.

scholarly journals CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Serap Bilge ◽  
Barış Ekici
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Interaction ◽  
Behavioral Problems ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Average Dose ◽  
The Core ◽  
Core Symptoms

Abstract Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

scholarly journals Microbiome-Specific Statistical Modeling Identifies Interplay Between Gastrointestinal Microbiome and Neurobehavioral Outcomes in Patients With Autism: A Case Control Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Minshi Huang ◽  
Jun Liu ◽  
Kevin Liu ◽  
Jierong Chen ◽  
Zhen Wei ◽  
...  
Keyword(s):  
Dietary Habits ◽  
Neurodevelopmental Disorder ◽  
Gastrointestinal Symptoms ◽  
Autism Spectrum ◽  
Case Control ◽  
Living Environment ◽  
Degree Relative ◽  
Gastrointestinal Microbiome ◽  
Core Symptoms ◽  
Tyrosine Biosynthesis

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear mechanisms of pathogenesis. Gastrointestinal microbiome alterations were found to correlate with ASD core symptoms, but its specific role in ASD pathogenesis has not been determined. In this study, we used a case-control strategy that simultaneously compared the ASD gastrointestinal microbiome with that from age-sex matched controls and first-degree relative controls, using a statistical framework accounting for confounders such as age. Enterobacteriaceae (including Escherichia/Shigella) and Phyllobacterium were significantly enriched in the ASD group, with their relative abundances all following a pattern of ASD > first degree relative control > healthy control, consistent with our hypothesis of living environment and shared microbial and immunological exposures as key drivers of ASD gastrointestinal microbiome dysbiosis. Using multivariable omnibus testing, we identified clinical factors including ADOS scores, dietary habits, and gastrointestinal symptoms that covary with overall microbiome structure within the ASD cohort. A microbiome-specific multivariate modeling approach (MaAsLin2) demonstrated microbial taxa, such as Lachnoclostridium and Tyzzerella, are significantly associated with ASD core symptoms measured by ADOS. Finally, we identified alterations in predicted biological functions, including tryptophan and tyrosine biosynthesis/metabolism potentially relevant to the pathophysiology of the gut-brain-axis. Overall, our results identified gastrointestinal microbiome signature changes in patients with ASD, highlighted associations between gastrointestinal microbiome and clinical characteristics related to the gut-brain axis and identified contributors to the heterogeneity of gastrointestinal microbiome within the ASD population.

scholarly journals The relationship of Rett syndrome and MECP2 disorders to autism

2012 ◽  
Vol 14 (3) ◽  
pp. 253-262 ◽  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Protein Product ◽  
The Many ◽  
Clinical Conditions ◽  
Relationship Of ◽  
The Relationship ◽  
Clinical Problems ◽  
Insight Into

Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.

scholarly journals Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder

2019 ◽  
Vol 20 (8) ◽  
pp. 1878 ◽  
Author(s):  
Rita Barone ◽  
Renata Rizzo ◽  
Giovanni Tabbì ◽  
Michele Malaguarnera ◽  
Richard E. Frye ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Neurodevelopmental Disorder ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Peroxisome Proliferator Activated Receptors

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by defective social communication and interaction and restricted, repetitive behavior with a complex, multifactorial etiology. Despite an increasing worldwide prevalence of ASD, there is currently no pharmacological cure to treat core symptoms of ASD. Clinical evidence and molecular data support the role of impaired mitochondrial fatty acid oxidation (FAO) in ASD. The recognition of defects in energy metabolism in ASD may be important for better understanding ASD and developing therapeutic intervention. The nuclear peroxisome proliferator-activated receptors (PPAR) α, δ, and γ are ligand-activated receptors with distinct physiological functions in regulating lipid and glucose metabolism, as well as inflammatory response. PPAR activation allows a coordinated up-regulation of numerous FAO enzymes, resulting in significant PPAR-driven increases in mitochondrial FAO flux. Resveratrol (RSV) is a polyphenolic compound which exhibits metabolic, antioxidant, and anti-inflammatory properties, pointing to possible applications in ASD therapeutics. In this study, we review the evidence for the existing links between ASD and impaired mitochondrial FAO and review the potential implications for regulation of mitochondrial FAO in ASD by PPAR activators, including RSV.

scholarly journals The Autism Palette: Combinations of Impairments Explain the Heterogeneity in ASD

2020 ◽  
Vol 11 ◽  
Author(s):  
Ábel Fóthi ◽  
Latha Soorya ◽  
András Lőrincz
Keyword(s):  
Strong Association ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Speech Communication ◽  
Compensatory Mechanisms ◽  
Restricted Interests ◽  
Cognitive Framework ◽  
Relevant Variables ◽  
The Many ◽  
Core Symptoms

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition traditionally defined by core symptoms in social behavior, speech/communication, repetitive behavior, and restricted interests. Beyond the core symptoms, autism has strong association with other disorders such as intellectual disability (ID), epilepsy, schizophrenia among many others. This paper outlines a theory of ASD with capacity to connect heterogeneous “core” symptoms, medical and psychiatric comorbidities as well as other etiological theories of autism in a unifying cognitive framework rooted in neuroscience and genetics. Cognition is embedded into an ever-developing structure modified by experiences, including the outcomes of environment influencing behaviors. The key constraint of cognition is that the brain can handle only 7±2 relevant variables at a time, whereas sensory variables, i.e., the number of sensory neurons is orders of magnitude larger. As a result, (a) the extraction, (b) the encoding, and (c) the capability for the efficient cognitive manipulation of the relevant variables, and (d) the compensatory mechanisms that counteract computational delays of the distributed components are critical. We outline our theoretical model to describe a Cartesian Factor (CF) forming, autoencoder-like cognitive mechanism which breaks combinatorial explosion and is accelerated by internal reinforcing machineries and discuss the neural processes that support CF formation. Impairments in any of these aspects may disrupt learning, cognitive manipulation, decisions on interactions, and execution of decisions. We suggest that social interactions are the most susceptible to combinations of diverse small impairments and can be spoiled in many ways that pile up. Comorbidity is experienced, if any of the many potential impairments is relatively strong. We consider component spoiling impairments as the basic colors of autism, whereas the combinations of individual impairments make the palette of autism. We put forth arguments on the possibility of dissociating the different main elements of the impairments that can appear together. For example, impairments of generalization (domain general learning) and impairments of dealing with many variable problems, such as social situations may appear independently and may mutually enhance their impacts. We also consider mechanisms that may lead to protection.

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