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

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.

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Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice

Nature Communications ◽

10.1038/s41467-021-23843-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Qian Wang ◽

Ying Kong ◽

Ding-Yu Wu ◽

Ji-Hong Liu ◽

Wei Jie ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Neurodevelopmental Disorder ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Conditional Knockout ◽

Spectrum Disorder ◽

Null Mutant ◽

Intracellular Ca ◽

Null Mutant Mice

AbstractAutism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular Ca2+ stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.

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Gut microbiota on gender bias in autism spectrum disorder

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0042 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Xia Hao ◽

Jiao Pan ◽

Xiumei Gao ◽

Shiyu Zhang ◽

Yue Li

Keyword(s):

Autism Spectrum Disorder ◽

Gut Microbiota ◽

Neurodevelopmental Disorder ◽

Repetitive Behavior ◽

Specific Treatment ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Communication Disorder ◽

Gender Dimorphism ◽

Men And Women

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Its three core symptoms are social communication disorder, communication disorder, narrow interest and stereotyped repetitive behavior. The proportion of male and female autistic patients is 4:1. Many researchers have studied this phenomenon, but the mechanism is still unclear. This review mainly discusses the related mechanism from the perspective of gut microbiota and introduces the influence of gut microbiota on the difference of ASD between men and women, as well as how gut microbiota may affect the gender dimorphism of ASD through metabolite of microbiota, immunity, and genetics, which provide some useful information for those who are interested in this research and find more gender-specific treatment for autistic men and women.

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Four Social Brain Regions, Their Dysfunctions, and Sequelae, Extensively Explain Autism Spectrum Disorder Symptomatology

Brain Sciences ◽

10.3390/brainsci9060130 ◽

2019 ◽

Vol 9 (6) ◽

pp. 130 ◽

Cited By ~ 1

Author(s):

Charles S. E. Weston

Keyword(s):

Autism Spectrum Disorder ◽

Brain Research ◽

Inferior Frontal Gyrus ◽

Research Question ◽

Neurodevelopmental Disorder ◽

Repetitive Behavior ◽

Brain Regions ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Social Brain

Autism spectrum disorder (ASD) is a challenging neurodevelopmental disorder with symptoms in social, language, sensory, motor, cognitive, emotional, repetitive behavior, and self-sufficient living domains. The important research question examined is the elucidation of the pathogenic neurocircuitry that underlies ASD symptomatology in all its richness and heterogeneity. The presented model builds on earlier social brain research, and hypothesizes that four social brain regions largely drive ASD symptomatology: amygdala, orbitofrontal cortex (OFC), temporoparietal cortex (TPC), and insula. The amygdala’s contributions to ASD largely derive from its major involvement in fine-grained intangible knowledge representations and high-level guidance of gaze. In addition, disrupted brain regions can drive disturbance of strongly interconnected brain regions to produce further symptoms. These and related effects are proposed to underlie abnormalities of the visual cortex, inferior frontal gyrus (IFG), caudate nucleus, and hippocampus as well as associated symptoms. The model is supported by neuroimaging, neuropsychological, neuroanatomical, cellular, physiological, and behavioral evidence. Collectively, the model proposes a novel, parsimonious, and empirically testable account of the pathogenic neurocircuitry of ASD, an extensive account of its symptomatology, a novel physiological biomarker with potential for earlier diagnosis, and novel experiments to further elucidate the mechanisms of brain abnormalities and symptomatology in ASD.

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Specialized Diet Therapies: Exploration for Improving Behavior in Autism Spectrum Disorder (ASD)

Current Medicinal Chemistry ◽

10.2174/0929867327666200217101908 ◽

2020 ◽

Vol 27 (40) ◽

pp. 6771-6786

Author(s):

Geir Bjørklund ◽

Nagwa Abdel Meguid ◽

Maryam Dadar ◽

Lyudmila Pivina ◽

Joanna Kałużna-Czaplińska ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Neurodevelopmental Disorder ◽

Caloric Intake ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Nutritional Deficiencies ◽

Childhood And Adolescence ◽

Restricted Interests ◽

Balanced Diet ◽

The Individual

As a major neurodevelopmental disorder, Autism Spectrum Disorder (ASD) encompasses deficits in communication and repetitive and restricted interests or behaviors in childhood and adolescence. Its etiology may come from either a genetic, epigenetic, neurological, hormonal, or an environmental cause, generating pathways that often altogether play a synergistic role in the development of ASD pathogenesis. Furthermore, the metabolic origin of ASD should be important as well. A balanced diet consisting of the essential and special nutrients, alongside the recommended caloric intake, is highly recommended to promote growth and development that withstand the physiologic and behavioral challenges experienced by ASD children. In this review paper, we evaluated many studies that show a relationship between ASD and diet to develop a better understanding of the specific effects of the overall diet and the individual nutrients required for this population. This review will add a comprehensive update of knowledge in the field and shed light on the possible nutritional deficiencies, metabolic impairments (particularly in the gut microbiome), and malnutrition in individuals with ASD, which should be recognized in order to maintain the improved socio-behavioral habit and physical health.

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

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

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.

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In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Toxics ◽

10.3390/toxics9050097 ◽

2021 ◽

Vol 9 (5) ◽

pp. 97

Author(s):

Tristan Furnary ◽

Rolando Garcia-Milian ◽

Zeyan Liew ◽

Shannon Whirledge ◽

Vasilis Vasiliou

Keyword(s):

Autism Spectrum Disorder ◽

Prenatal Exposure ◽

Pesticide Exposure ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Biomedical Literature ◽

Spectrum Disorder ◽

Biological Processes ◽

Genetic Associations ◽

Increased Risk

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

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Mealtime Behaviors and Food Preferences of Students with Autism Spectrum Disorder

Foods ◽

10.3390/foods10010049 ◽

2020 ◽

Vol 10 (1) ◽

pp. 49

Author(s):

Hae Jin Park ◽

Su Jin Choi ◽

Yuri Kim ◽

Mi Sook Cho ◽

Yu-Ri Kim ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Nutrition Education ◽

Neurodevelopmental Disorder ◽

Food Preferences ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Online Questionnaire ◽

Mealtime Behavior ◽

High Level

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a lack of social communication and restrictive, repetitive behaviors or interests. This study aimed to examine the mealtime behaviors and food preferences of students with ASD. An online questionnaire on mealtime behavior and food preferences of ASD students was conducted by caregivers including parents, and the average age of ASD students was 14.1 ± 6.1. The analysis of mealtime behavior resulted in classification into three clusters: cluster 1, the “low-level problematic mealtime behavior group”; cluster 2, the “mid-level problematic mealtime behavior group”; and cluster 3, the “high-level problematic mealtime behavior group”. Cluster 1 included older students than other clusters and their own specific dietary rituals. Meanwhile, cluster 3 included younger students than other clusters, high-level problematic mealtime behavior, and a low preference for food. In particular, there were significant differences in age and food preference for each subdivided ASD group according to their eating behaviors. Therefore, the content and method of nutrition education for ASD students’ needs a detailed approach according to the characteristics of each group.

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The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17

International Journal of Molecular Sciences ◽

10.3390/ijms22010118 ◽

2020 ◽

Vol 22 (1) ◽

pp. 118

Author(s):

Yuanpeng Zheng ◽

Tessa A. Verhoeff ◽

Paula Perez Pardo ◽

Johan Garssen ◽

Aletta D. Kraneveld

Keyword(s):

Autism Spectrum Disorder ◽

Intestinal Tract ◽

Synapse Formation ◽

Inflammatory Responses ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Protein Substrates ◽

Specific Proteins ◽

Membrane Bound

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut–brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut–brain axis.

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Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽

10.3390/genes12071053 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1053

Author(s):

Jasleen Dhaliwal ◽

Ying Qiao ◽

Kristina Calli ◽

Sally Martell ◽

Simone Race ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Variable Effect ◽

Gabaergic Neurotransmission ◽

High Heritability ◽

Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

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Perceptions of Autism Spectrum Disorder (ASD) Etiology among Parents of Children with ASD

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18136774 ◽

2021 ◽

Vol 18 (13) ◽

pp. 6774

Author(s):

Wei-Ju Chen ◽

Zihan Zhang ◽

Haocen Wang ◽

Tung-Sung Tseng ◽

Ping Ma ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Content Analysis ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Parental Perceptions ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Structured Interviews ◽

Children With Asd ◽

Religious Factors

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and restricted or repetitive behaviors. Parental perceptions of the etiology of their child’s ASD can affect provider–client relationships, bonding between parents and their children, and the prognosis, treatment, and management of children with ASD. Thus, this study sought to examine the perceptions of ASD etiology of parents of children with ASD. Methods: Forty-two parents of children diagnosed with ASD were recruited across Texas. Semi-structured interviews were conducted individually. All interviews were recorded and later transcribed verbatim for content analysis utilizing NVivo 12.0 (QSR International, Doncaster, Australia). Results: The content analysis identified the following themes regarding parental perceptions of ASD etiology: Genetic factors (40.5%), environmental factors (31.0%), problems that occurred during pregnancy or delivery (23.8%), vaccinations (16.7%), other health problems (7.1%), parental age at the time of pregnancy (4.8%), and spiritual or religious factors (2.4%). Conclusions: The parental perceptions of ASD etiology were diverse, but several views, such as vaccinations and spiritual or religious factors, were not based on scientific evidence. Health professionals and researchers can use these findings to develop and provide targeted education to parents who have children with ASD. Our findings also support policymakers in developing campaigns designed to increase parental ASD awareness and knowledge.

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