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Pathogenesis and Treatment of Autism Spectrum Disorders 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (10 December 2022) | Viewed by 43631

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Special Issue Editor

Prof. Dr. Kunio Yui

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Guest Editor

Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan
Interests: autism; antioxidant protein; oxidtive stress; tuberous sclerosis; cell mechanism of signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

These are some of the most interesting and important findings on the pathophysiology of autism related to pharmacological care: (1) α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors can be a potential target for the treatment of social behavior deficits in autism spectrum disorders (ASDs). (2) The Rho family GTPases-activating proteins transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. (3) The pharmaceutical value of gut peptide hormones in alleviating autism-associated behavioral syndromes in providing new insights for future drug development. (4) Perturbation of these processes of mRNA targeting and local protein synthesis in stem-cell-derived neurons may influence synapse development and functions related to cognitive deficits in ASD.

The investigation of links between the ratio of omega-3/omega-6 PUFAs and neuronal signaling is a research priority in autism spectrum disorders (ASDs). Increased plasma DHA/arachidonic acid (AA) ratios may induce low plasma levels of ceruloplasmin. Reduced plasma ceruloplasmin levels may diminish the protective capacity against brain damage, contributing to the pathophysiology of social symptoms in individuals with ASD. Additionally, large doses of AA added to DHA have been shown to improve ASD social impairment with increased plasma ceruloplasmin levels. We welcome papers dealing with any of these topics.

Prof. Dr. Kunio Yui
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

autism
arachidonic acid
signaling mediators
social impairment
drug targets

Published Papers (7 papers)

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Research

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18 pages, 2080 KiB

Open AccessArticle

Peripubertal Alterations of Leptin Levels in Patients with Autism Spectrum Disorder and Elevated or Normal Body Weight

by Katarzyna E. Skórzyńska-Dziduszko, Agata Makarewicz and Anna Błażewicz

Int. J. Mol. Sci. 2023, 24(5), 4878; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054878 - 02 Mar 2023

Viewed by 1324

Abstract

Leptin, which plays a key role in energy homeostasis, is known as a neurotrophic factor possibly linking nutrition and neurodevelopment. Available data on the association between leptin and autism spectrum disorder (ASD) are confusing. The aim of this study was to explore whether plasma levels of leptin in pre- and post-pubertal children with ASD and/or overweightness/obesity differ from those of BMI- and age-matched healthy controls. Leptin levels were determined in 287 pre-pubertal children (mean age 8.09 years), classified as follows: ASD with overweightness/obesity (ASD+/Ob+); ASD without overweightness/obesity (ASD+/Ob−); non-ASD with overweightness/obesity (ASD−/Ob+); non-ASD without overweightness/obesity (ASD−/Ob−). The assessment was repeated in 258 of the children post-pubertally (mean age 14.26 years). There were no significant differences in leptin levels either before or after puberty between ASD+/Ob+ and ASD−/Ob+ or between ASD+/Ob− and ASD−/Ob−, although there was a strong trend toward significance for higher pre-pubertal leptin levels in ASD+/Ob− than in ASD−/Ob−. Post-pubertal leptin levels were significantly lower than pre-pubertal levels in ASD+/Ob+, ASD−/Ob+, and ASD+/Ob− and higher in ASD−/Ob−. Leptin levels, elevated pre-pubertally in the children with overweightness/obesity as well as in children with ASD and normal BMI, decrease with age, in contrast to the increasing leptin levels in healthy controls. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Autism Spectrum Disorders 2.0)

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Review

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16 pages, 1143 KiB

Open AccessReview

Prenatal Sex Hormone Exposure Is Associated with the Development of Autism Spectrum Disorder

by Mengwei Li, Noriyoshi Usui and Shoichi Shimada

Int. J. Mol. Sci. 2023, 24(3), 2203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032203 - 22 Jan 2023

Cited by 5 | Viewed by 4216

Abstract

Sexual differentiation is a major developmental process. Sex differences resulting from sexual differentiation have attracted the attention of researchers. Unraveling what contributes to and underlies sex differences will provide valuable insights into the development of neurodevelopmental disorders that exhibit sex biases. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects an individual’s social interaction and communication abilities, and its male preponderance has been consistently reported in clinical studies. The etiology of male preponderance remains unclear, but progress has been made in studying prenatal sex hormone exposure. The present review examined studies that focused on the association between prenatal testosterone exposure and ASD development, as well as sex-specific behaviors in individuals with ASD. This review also included studies on maternal immune activation-induced developmental abnormalities that also showed striking sex differences in offspring and discussed its possible interacting roles in ASD so as to present a potential approach for future studies on sex biases in ASD. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Autism Spectrum Disorders 2.0)

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20 pages, 1756 KiB

Open AccessReview

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder

by Kunio Yui, George Imataka and Shigemi Yoshihara

Int. J. Mol. Sci. 2022, 23(17), 9803; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179803 - 29 Aug 2022

Cited by 8 | Viewed by 3159

Abstract

The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation–reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Autism Spectrum Disorders 2.0)

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34 pages, 2183 KiB

Open AccessReview

The Cerebellar Involvement in Autism Spectrum Disorders: From the Social Brain to Mouse Models

by Lisa Mapelli, Teresa Soda, Egidio D’Angelo and Francesca Prestori

Int. J. Mol. Sci. 2022, 23(7), 3894; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073894 - 31 Mar 2022

Cited by 31 | Viewed by 6584

Abstract

Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders that include a variety of forms and clinical phenotypes. This heterogeneity complicates the clinical and experimental approaches to ASD etiology and pathophysiology. To date, a unifying theory of these diseases is still missing. Nevertheless, the intense work of researchers and clinicians in the last decades has identified some ASD hallmarks and the primary brain areas involved. Not surprisingly, the areas that are part of the so-called “social brain”, and those strictly connected to them, were found to be crucial, such as the prefrontal cortex, amygdala, hippocampus, limbic system, and dopaminergic pathways. With the recent acknowledgment of the cerebellar contribution to cognitive functions and the social brain, its involvement in ASD has become unmistakable, though its extent is still to be elucidated. In most cases, significant advances were made possible by recent technological developments in structural/functional assessment of the human brain and by using mouse models of ASD. Mouse models are an invaluable tool to get insights into the molecular and cellular counterparts of the disease, acting on the specific genetic background generating ASD-like phenotype. Given the multifaceted nature of ASD and related studies, it is often difficult to navigate the literature and limit the huge content to specific questions. This review fulfills the need for an organized, clear, and state-of-the-art perspective on cerebellar involvement in ASD, from its connections to the social brain areas (which are the primary sites of ASD impairments) to the use of monogenic mouse models. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Autism Spectrum Disorders 2.0)

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25 pages, 1353 KiB

Open AccessReview

Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?

by Maria de los Angeles Robinson-Agramonte, Elena Noris García, Jarasca Fraga Guerra, Yamilé Vega Hurtado, Nicola Antonucci, Neomar Semprún-Hernández, Stephen Schultz and Dario Siniscalco

Int. J. Mol. Sci. 2022, 23(6), 3033; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063033 - 11 Mar 2022

Cited by 43 | Viewed by 8165

Abstract

Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental disorders characterized by a wide and variable set of neuropsychiatric symptoms, including deficits in social communication, narrow and restricted interests, and repetitive behavior. The immune hypothesis is considered to be a major factor contributing to autism pathogenesis, as well as a way to explain the differences of the clinical phenotypes and comorbidities influencing disease course and severity. Evidence highlights a link between immune dysfunction and behavioral traits in autism from several types of evidence found in both cerebrospinal fluid and peripheral blood and their utility to identify autistic subgroups with specific immunophenotypes; underlying behavioral symptoms are also shown. This review summarizes current insights into immune dysfunction in ASD, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity. Finally, we described main elements of similarities between immunopathology overlapping neurodevelopmental and neurodegenerative disorders, taking as examples autism and Parkinson Disease, respectively. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Autism Spectrum Disorders 2.0)

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22 pages, 1668 KiB

Open AccessReview

The Human Gut Microbiome as a Potential Factor in Autism Spectrum Disorder

by Amani Alharthi, Safiah Alhazmi, Najla Alburae and Ahmed Bahieldin

Int. J. Mol. Sci. 2022, 23(3), 1363; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031363 - 25 Jan 2022

Cited by 29 | Viewed by 10685

Abstract

The high prevalence of gastrointestinal (GI) disorders among autism spectrum disorder (ASD) patients has prompted scientists to look into the gut microbiota as a putative trigger in ASD pathogenesis. Thus, many studies have linked the gut microbial dysbiosis that is frequently observed in ASD patients with the modulation of brain function and social behavior, but little is known about this connection and its contribution to the etiology of ASD. This present review highlights the potential role of the microbiota–gut–brain axis in autism. In particular, it focuses on how gut microbiota dysbiosis may impact gut permeability, immune function, and the microbial metabolites in autistic people. We further discuss recent findings supporting the possible role of the gut microbiome in initiating epigenetic modifications and consider the potential role of this pathway in influencing the severity of ASD. Lastly, we summarize recent updates in microbiota-targeted therapies such as probiotics, prebiotics, dietary supplements, fecal microbiota transplantation, and microbiota transfer therapy. The findings of this paper reveal new insights into possible therapeutic interventions that may be used to reduce and cure ASD-related symptoms. However, well-designed research studies using large sample sizes are still required in this area of study. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Autism Spectrum Disorders 2.0)

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22 pages, 639 KiB

Open AccessReview

The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and Implications for Treatment

by Aleksandra Zawadzka, Magdalena Cieślik and Agata Adamczyk

Int. J. Mol. Sci. 2021, 22(21), 11516; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111516 - 26 Oct 2021

Cited by 48 | Viewed by 8351

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disease that is characterized by a deficit in social interactions and communication, as well as repetitive and restrictive behaviors. Increasing lines of evidence suggest an important role for immune dysregulation and/or inflammation in the development of ASD. Recently, a relationship between inflammation, oxidative stress, and mitochondrial dysfunction has been reported in the brain tissue of individuals with ASD. Some recent studies have also reported oxidative stress and mitochondrial abnormalities in animal models of maternal immune activation (MIA). This review is focused on the hypothesis that MIA induces microglial activation, oxidative stress, and mitochondrial dysfunction, a deleterious trio in the brain that can lead to neuroinflammation and neurodevelopmental pathologies in offspring. Infection during pregnancy activates the mother’s immune system to release proinflammatory cytokines, such as IL-6, TNF-α, and others. Furthermore, these cytokines can directly cross the placenta and enter the fetal circulation, or activate resident immune cells, resulting in an increased production of proinflammatory cytokines, including IL-6. Proinflammatory cytokines that cross the blood–brain barrier (BBB) may initiate a neuroinflammation cascade, starting with the activation of the microglia. Inflammatory processes induce oxidative stress and mitochondrial dysfunction that, in turn, may exacerbate oxidative stress in a self-perpetuating vicious cycle that can lead to downstream abnormalities in brain development and behavior. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Autism Spectrum Disorders 2.0)

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