Molecular Mechanisms of Autism Spectrum Disorder

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: 20 October 2025 | Viewed by 7722

Special Issue Editors


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Guest Editor
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70806, USA
Interests: autism spectrum disorder; neurodevelopmental disorders; molecular and cellular mechanisms; neurobiological mechanisms; treatment approaches; intervention strategies; behavioral and neuroanatomical alterations

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Guest Editor
School of Veterinary Medicine, Baton Rouge, LA, USA
Interests: neuron; perineuronal net; synapse; membrane; glia; morphology; thalamus; cortex; inferior colliculus; auditory; sensory; neurodegeneration; neurodevelopment

Special Issue Information

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social interaction and communication deficits, repetitive, restricted behaviors, and variable co-morbid conditions. The etiological heterogeneity of ASD encompasses complex interactions of genetic, immunological, and environmental factors that result in alterations to brain function and structure, which influence the onset of these conditions. The emergence of ASD is influenced by several molecular mechanisms that are the focus of diagnostic and intervention strategies; however, our understanding of these mechanisms remains incomplete. Such heterogeneous etiological factors contribute greatly to the development, prognosis, and variability of autistic traits.

This Special Issue aims to assemble original research and literature reviews that address the latest developments in the molecular mechanisms of autism spectrum disorder. We hope that contributions to this Special Issue will have a significant impact on ASD research in terms of understanding its molecular etiology and developing novel therapeutic strategies.

Dr. Tanya Gandhi
Dr. Charles Lee
Guest Editors

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Keywords

  • autism spectrum disorder
  • neurodevelopmental disorders
  • molecular mechanisms
  • cellular-molecular mechanisms
  • neurobiological mechanisms
  • neural mechanisms
  • intervention approaches
  • treatment strategies

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Published Papers (4 papers)

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Research

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20 pages, 10684 KiB  
Article
Environmental Enrichment Attenuates Repetitive Behavior and Alters the Functional Connectivity of Pain and Sensory Pathways in C58 Mice
by Anna L. Farmer, Marcelo Febo, Bradley J. Wilkes and Mark H. Lewis
Cells 2024, 13(23), 1933; https://doi.org/10.3390/cells13231933 - 21 Nov 2024
Viewed by 1223
Abstract
Restricted repetitive behaviors (RRB) encompass a variety of inflexible behaviors, which are diagnostic for autism spectrum disorder (ASD). Despite being requisite diagnostic criteria, the neurocircuitry of these behaviors remains poorly understood, limiting treatment development. Studies in translational animal models show environmental enrichment (EE) [...] Read more.
Restricted repetitive behaviors (RRB) encompass a variety of inflexible behaviors, which are diagnostic for autism spectrum disorder (ASD). Despite being requisite diagnostic criteria, the neurocircuitry of these behaviors remains poorly understood, limiting treatment development. Studies in translational animal models show environmental enrichment (EE) reduces the expression of RRB, although the underlying mechanisms are largely unknown. This study used functional magnetic resonance imaging to identify functional connectivity alterations associated with RRB and its attenuation by EE in C58 mice, an animal model of RRB. Extensive differences were observed between C58 mice and C57BL/6 control mice. Higher RRB was associated with altered connectivity between the somatosensory network and reticular thalamic nucleus and between striatal and sensory processing regions. Animals housed in EE displayed increased connectivity between the somatosensory network and the anterior pretectal nucleus and hippocampus, as well as reduced connectivity between the visual network and area prostriata. These results suggest aberrant sensory perception is associated with RRB in C58 mice. EE may reduce RRB by altering functional connectivity in pain and visual networks. This study raises questions about the role of sensory processing and pain in RRB development and identifies new potential intervention targets. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Autism Spectrum Disorder)
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26 pages, 46310 KiB  
Article
iPSC-Derived Astrocytes and Neurons Replicate Brain Gene Expression, Epigenetic, Cell Morphology and Connectivity Alterations Found in Autism
by Hamid Mostafavi Abdolmaleky, Reza Alam, Shabnam Nohesara, Richard C. Deth and Jin-Rong Zhou
Cells 2024, 13(13), 1095; https://doi.org/10.3390/cells13131095 - 25 Jun 2024
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Abstract
Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging. Methods: We used iPSC-derived [...] Read more.
Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging. Methods: We used iPSC-derived neurons and astrocytes of patients with autism vs. controls (5/group) to examine whether they replicate the postmortem brain expression/epigenetic alterations of autism. Additionally, DNA methylation of 10 postmortem brain samples (5/group) was analyzed for genes affected in PSC-derived cells. Results: We found hyperexpression of TGFB1, TGFB2, IL6 and IFI16 and decreased expression of HAP1, SIRT1, NURR1, RELN, GPX1, EN2, SLC1A2 and SLC1A3 in the astrocytes of patients with autism, along with DNA hypomethylation of TGFB2, IL6, TNFA and EN2 gene promoters and a decrease in HAP1 promoter 5-hydroxymethylation in the astrocytes of patients with autism. In neurons, HAP1 and IL6 expression trended alike. While HAP1 promoter was hypermethylated in neurons, IFI16 and SLC1A3 promoters were hypomethylated and TGFB2 exhibited increased promoter 5-hydroxymethlation. We also found a reduction in neuronal arborization, spine size, growth rate, and migration, but increased astrocyte size and a reduced growth rate in autism. In postmortem brain samples, we found DNA hypomethylation of TGFB2 and IFI16 promoter regions, but DNA hypermethylation of HAP1 and SLC1A2 promoters in autism. Conclusion: Autism-associated expression/epigenetic alterations in iPSC-derived cells replicated those reported in the literature, making them appropriate surrogates to study disease pathogenesis or patient-specific therapeutics. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Autism Spectrum Disorder)
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Review

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22 pages, 1188 KiB  
Review
Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction
by Julia Lopes Gonçalez, Jenny Shen and Wei Li
Cells 2024, 13(24), 2077; https://doi.org/10.3390/cells13242077 - 17 Dec 2024
Cited by 1 | Viewed by 1869
Abstract
Rett syndrome (RTT), which predominantly affects females, arises in most cases from mutations in the Methyl-CpG-binding Protein-2 (MECP2) gene. When MeCP2 is impaired, it disrupts the regulation of numerous genes, causing the production of dysfunctional proteins associated with various multi-systemic issues [...] Read more.
Rett syndrome (RTT), which predominantly affects females, arises in most cases from mutations in the Methyl-CpG-binding Protein-2 (MECP2) gene. When MeCP2 is impaired, it disrupts the regulation of numerous genes, causing the production of dysfunctional proteins associated with various multi-systemic issues in RTT. In this review, we explore the current insights into molecular signaling related to monoamines, immune response, and mitochondrial function, and their implications for the pathophysiology of RTT. Research has shown that monoamines—such as dopamine, norepinephrine, epinephrine, serotonin, and histamine—exhibit alterations in RTT, contributing to a range of neurological symptoms. Furthermore, the immune system in RTT individuals demonstrates dysfunction through the abnormal activity of microglia, macrophages, lymphocytes, and non-immune cells, leading to the atypical release of inflammatory mediators and disruptions in the NF-κB signaling pathway. Moreover, mitochondria, essential for energy production and calcium storage, also show dysfunction in this condition. The delicate balance of producing and scavenging reactive oxygen species—termed redox balance—is disrupted in RTT. Targeting these molecular pathways presents a promising avenue for developing effective therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Autism Spectrum Disorder)
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Other

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11 pages, 433 KiB  
Commentary
Neurodevelopment of Autism: Critical Periods, Stress and Nutrition
by George Ayoub
Cells 2024, 13(23), 1968; https://doi.org/10.3390/cells13231968 - 28 Nov 2024
Viewed by 1705
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disability that presents significant challenges in communication and behavior. ASD prevalence exceeds 2% among eight-year-old children and is at similar levels globally. We propose that critical periods during fetal development and early postnatal years establish the [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental disability that presents significant challenges in communication and behavior. ASD prevalence exceeds 2% among eight-year-old children and is at similar levels globally. We propose that critical periods during fetal development and early postnatal years establish the conditions for either neurotypical development or the emergence of autism through mechanisms that influence immune function or delay neuronal development. One critical period is characterized by the requirement for folate, a crucial methyl donor needed for DNA regulation. Insufficient folate availability has been linked to the risk of developing ASD. Another critical period may be affected by oxidative stress or inflammation of the fetal brain, potentially due to inadequate microglial immunity, which can lead to CNS inflammatory changes that disrupt typical neurodevelopment. We suggest that early supplementation with reduced folate and taurine during both the fetal and postnatal stages may be effective in mitigating the severity of ASD symptoms by promoting neurotypical development through these critical neurodevelopmental periods. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Autism Spectrum Disorder)
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