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Pathogenesis and Treatment of Autism Spectrum Disorders

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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 (30 April 2021) | Viewed by 22797

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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,

There are most interesting and important findings on 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 (ASD); (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 will be discussed to provide new insights for future drug development; (4) Perturbation of these processes of mRNA targeting and local protein synthesis in stem cell-derived neurons may 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 (ASD). 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. Also, large doses of AA added to DHA improved ASD social impairment with increased plasma ceruloplasmin levels.

Prof. Dr. Kunio Yui
Guest Editor

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Keywords

autism
arachidonic acid
signaling mediators
social impairment
drug targets

Published Papers (6 papers)

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Research

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34 pages, 8124 KiB

Open AccessArticle

Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid

by Magdalena Gąssowska-Dobrowolska, Agnieszka Kolasa-Wołosiuk, Magdalena Cieślik, Agnieszka Dominiak, Kristina Friedland and Agata Adamczyk

Int. J. Mol. Sci. 2021, 22(6), 3209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063209 - 22 Mar 2021

Cited by 19 | Viewed by 3668

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction and communication besides repetitive, stereotyped behaviours. A characteristic feature of ASD is altered dendritic spine density and morphology associated with synaptic plasticity disturbances. Since microtubules (MTs) regulate dendritic spine morphology and play an important role in spine development and plasticity the aim of the present study was to investigate the alterations in the content of neuronal α/β-tubulin and Tau protein level as well as phosphorylation state in the valproic acid (VPA)-induced rat model of autism. Our results indicated that maternal exposure to VPA induces: (1) decrease the level of α/β-tubulin along with Tau accumulation in the hippocampus and cerebral cortex; (2) excessive Tau phosphorylation and activation of Tau-kinases: CDK5, ERK1/2, and p70S6K in the cerebral cortex; (3) up-regulation of mTOR kinase-dependent signalling in the hippocampus and cerebral cortex of adolescent rat offspring. Moreover, immunohistochemical staining showed histopathological changes in neurons (chromatolysis) in both analysed brain structures of rats prenatally exposed to VPA. The observed changes in Tau protein together with an excessive decrease in α/β-tubulin level may suggest destabilization and thus dysfunction of the MT cytoskeleton network, which in consequence may lead to the disturbance in synaptic plasticity and the development of autistic-like behaviours. Full article

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

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12 pages, 1025 KiB

Open AccessArticle

Shorter P1m Response in Children with Autism Spectrum Disorder without Intellectual Disabilities

by Yuko Yoshimura, Takashi Ikeda, Chiaki Hasegawa, Kyung-Min An, Sanae Tanaka, Ken Yaoi, Sumie Iwasaki, Daisuke N. Saito, Hirokazu Kumazaki, Hirotoshi Hiraishi and Mitsuru Kikuchi

Int. J. Mol. Sci. 2021, 22(5), 2611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052611 - 05 Mar 2021

Cited by 7 | Viewed by 3265

Abstract

(1) Background: Atypical auditory perception has been reported in individuals with autism spectrum disorder (ASD). Altered auditory evoked brain responses are also associated with childhood ASD. They are likely to be associated with atypical brain maturation. (2) Methods: This study examined children aged 5–8 years old: 29 with ASD but no intellectual disability and 46 age-matched typically developed (TD) control participants. Using magnetoencephalography (MEG) data obtained while participants listened passively to sinusoidal pure tones, bilateral auditory cortical response (P1m) was examined. (3) Results: Significantly shorter P1m latency in the left hemisphere was found for children with ASD without intellectual disabilities than for children with TD. Significant correlation between P1m latency and language conceptual ability was found in children with ASD, but not in children with TD. (4) Conclusions: These findings demonstrated atypical brain maturation in the auditory processing area in children with ASD without intellectual disability. Findings also suggest that ASD has a common neural basis for pure-tone sound processing and language development. Development of brain networks involved in language concepts in early childhood ASD might differ from that in children with TD. Full article

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

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21 pages, 1535 KiB

Open AccessArticle

The Multi-Targeting Ligand ST-2223 with Histamine H₃ Receptor and Dopamine D₂/D₃ Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice

by Nermin Eissa, Karthikkumar Venkatachalam, Petrilla Jayaprakash, Markus Falkenstein, Mariam Dubiel, Annika Frank, David Reiner-Link, Holger Stark and Bassem Sadek

Int. J. Mol. Sci. 2021, 22(4), 1947; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041947 - 16 Feb 2021

Cited by 15 | Viewed by 2734

Abstract

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H₃ receptor (H₃R) and dopamine D₂/D₃ receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data. Full article

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

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Review

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18 pages, 1217 KiB

Open AccessReview

Dissecting Molecular Genetic Mechanisms of 1q21.1 CNV in Neuropsychiatric Disorders

by Joy Yoon and Yingwei Mao

Int. J. Mol. Sci. 2021, 22(11), 5811; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115811 - 28 May 2021

Cited by 6 | Viewed by 5313

Abstract

Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance. Full article

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

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19 pages, 725 KiB

Open AccessReview

The Role of Cholesterol and Fatty Acids in the Etiology and Diagnosis of Autism Spectrum Disorders

by Cecilia Maria Esposito, Massimiliano Buoli, Valentina Ciappolino, Carlo Agostoni and Paolo Brambilla

Int. J. Mol. Sci. 2021, 22(7), 3550; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073550 - 29 Mar 2021

Cited by 16 | Viewed by 3194

Abstract

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders whose pathogenesis seems to be related to an imbalance of excitatory and inhibitory synapses, which leads to disrupted connectivity during brain development. Among the various biomarkers that have been evaluated in the last years, metabolic factors represent a bridge between genetic vulnerability and environmental aspects. In particular, cholesterol homeostasis and circulating fatty acids seem to be involved in the pathogenesis of ASDs, both through the contribute in the stabilization of cell membranes and the modulation of inflammatory factors. The purpose of the present review is to summarize the available data about the role of cholesterol and fatty acids, mainly long-chain ones, in the onset of ASDs. A bibliographic research on the main databases was performed and 36 studies were included in our review. Most of the studies document a correlation between ASDs and hypocholesterolemia, while the results concerning circulating fatty acids are less univocal. Even though further studies are necessary to confirm the available data, the metabolic biomarkers open to new treatment options such as the modulation of the lipid pattern through the diet. Full article

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

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14 pages, 2290 KiB

Open AccessReview

Local Protein Translation and RNA Processing of Synaptic Proteins in Autism Spectrum Disorder

by Yuyoung Joo and David R. Benavides

Int. J. Mol. Sci. 2021, 22(6), 2811; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062811 - 10 Mar 2021

Cited by 13 | Viewed by 3394

Abstract

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition associated with impairments in social interaction, communication and repetitive behaviors. While the underlying disease mechanisms remain to be fully elucidated, dysfunction of neuronal plasticity and local translation control have emerged as key points of interest. Translation of mRNAs for critical synaptic proteins are negatively regulated by Fragile X mental retardation protein (FMRP), which is lost in the most common single-gene disorder associated with ASD. Numerous studies have shown that mRNA transport, RNA metabolism, and translation of synaptic proteins are important for neuronal health, synaptic plasticity, and learning and memory. Accordingly, dysfunction of these mechanisms may contribute to the abnormal brain function observed in individuals with autism spectrum disorder (ASD). In this review, we summarize recent studies about local translation and mRNA processing of synaptic proteins and discuss how perturbations of these processes may be related to the pathophysiology of ASD. Full article

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

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