International Journal of Molecular Sciences

Research

Jump to: Review

18 pages, 4118 KiB

Open AccessArticle

Exogenous IL-17A Alleviates Social Behavior Deficits and Increases Neurogenesis in a Murine Model of Autism Spectrum Disorders

by Yehoshua Willinger, Daniella R. Friedland Cohen and Gadi Turgeman

Int. J. Mol. Sci. 2024, 25(1), 432; https://doi.org/10.3390/ijms25010432 - 28 Dec 2023

Viewed by 935

Abstract

Among the proposed mechanisms for autism spectrum disorders (ASD) is immune dysregulation. The proinflammatory cytokine Interleukine-17A (IL-17A) was shown to play a key role in mediating immune-related neurodevelopmental impairment of social behavior. Nevertheless, post-developmental administration of IL-17A was found to increase social behavior. [...] Read more.

Among the proposed mechanisms for autism spectrum disorders (ASD) is immune dysregulation. The proinflammatory cytokine Interleukine-17A (IL-17A) was shown to play a key role in mediating immune-related neurodevelopmental impairment of social behavior. Nevertheless, post-developmental administration of IL-17A was found to increase social behavior. In the present study, we explored the effect of post-developmental administration of IL-17A on ASD-like behaviors induced by developmental exposure to valproic acid (VPA) at postnatal day 4. At the age of seven weeks, VPA-exposed mice were intravenously injected twice with recombinant murine IL-17A (8 μg), and a week later, they were assessed for ASD-like behavior. IL-17A administration increased social behavior and alleviated the ASD-like phenotype. Behavioral changes were associated with increased serum levels of IL-17 and Th17-related cytokines. Exogenous IL-17A also increased neuritogenesis in the dendritic tree of doublecortin-expressing newly formed neurons in the dentate gyrus. Interestingly, the effect of IL-17A on neuritogenesis was more noticeable in females than in males, suggesting a sex-dependent effect of IL-17A. In conclusion, our study suggests a complex role for IL-17A in ASD. While contributing to its pathology at the developmental stage, IL-17 may also promote the alleviation of behavioral deficits post-developmentally by promoting neuritogenesis and synaptogenesis in the dentate gyrus. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Figure 1

18 pages, 3147 KiB

Open AccessArticle

Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice

by Pamela R. Westmark, Aaron K. Gholston, Timothy J. Swietlik, Rama K. Maganti and Cara J. Westmark

Int. J. Mol. Sci. 2023, 24(19), 14460; https://doi.org/10.3390/ijms241914460 - 22 Sep 2023

Cited by 1 | Viewed by 1446

Abstract

Nearly half of children with fragile X syndrome experience sleep problems including trouble falling asleep and frequent nighttime awakenings. The goals here were to assess sleep–wake cycles in mice in response to Fmr1 genotype and a dietary intervention that reduces hyperactivity. Electroencephalography (EEG) [...] Read more.

Nearly half of children with fragile X syndrome experience sleep problems including trouble falling asleep and frequent nighttime awakenings. The goals here were to assess sleep–wake cycles in mice in response to Fmr1 genotype and a dietary intervention that reduces hyperactivity. Electroencephalography (EEG) results were compared with published rest–activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. Specifically, sleep–wake patterns in adult wild type and Fmr1^KO littermate mice were recorded after EEG electrode implantation and the recordings manually scored for vigilance states. The data indicated that Fmr1^KO mice exhibited sleep–wake patterns similar to wild type littermates when maintained on a control purified ingredient diet. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of non-rapid eye movement (NREM) sleep in both wild type and Fmr1^KO mice during the dark cycle, which corresponded to decreased activity levels. Treatment with a ketogenic diet flattened diurnal sleep periodicity in both wild type and Fmr1^KO mice. Differences in several sleep microstructure outcomes (number and length of sleep and wake bouts) supported the altered sleep states in response to a ketogenic diet and were correlated with altered rest–activity cycles. While actigraphy may be a less expensive, reduced labor surrogate for sleep EEG during the dark cycle, daytime resting in mice did not correlate with EEG sleep states. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Figure 1

18 pages, 2879 KiB

Open AccessArticle

Salivary Oxytocin and Antioxidative Response to Robotic Touch in Adults with Autism Spectrum Disorder

by Galina V. Portnova, Elena V. Proskurnina, Ivan V. Skorokhodov, Svetlana V. Sokolova, Alexey N. Semirechenko and Anton A. Varlamov

Int. J. Mol. Sci. 2023, 24(15), 12322; https://doi.org/10.3390/ijms241512322 - 1 Aug 2023

Viewed by 1392

Abstract

Individuals with ASD are known to have a tendency to have tactile sensory processing issues that could be associated with their impairment as regards social communication. The alterations in tactile processing in autistic subjects are usually accompanied by hypersensitivity and other unpleasant emotions [...] Read more.

Individuals with ASD are known to have a tendency to have tactile sensory processing issues that could be associated with their impairment as regards social communication. The alterations in tactile processing in autistic subjects are usually accompanied by hypersensitivity and other unpleasant emotions induced by tactile contact. In our study, we investigated the impact of the velocity and the force of a tactile stroke received impersonally by a custom-built robotic device. A total of 21 adults with ASD and 22 adults from a control group participated in our study. The participants’ responses were assessed according to subjective scales, EEG changes, and the dynamics of saliva antioxidants and oxytocin. It was found that the oxytocin level was significantly lower in subjects with ASD but increased after tactile stimulation. However, contrary to expectations, the increase in the oxytocin level in the target group negatively correlated with the subjective pleasantness of tactile stimulation and was probably associated with a stress-induced effect. The basic levels of antioxidants did not differ between the TD and ASD groups; however, these had significantly increased in individuals with ASD by the end of the study. The EEG findings, which revealed enhanced antioxidant levels, contributed to the relief of the cognitive control during the study. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Graphical abstract

23 pages, 6519 KiB

Open AccessArticle

Microtubule Cytoskeletal Network Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders

by Magdalena Gąssowska-Dobrowolska, Grzegorz A. Czapski, Magdalena Cieślik, Karolina Zajdel, Małgorzata Frontczak-Baniewicz, Lidia Babiec and Agata Adamczyk

Int. J. Mol. Sci. 2023, 24(8), 7303; https://doi.org/10.3390/ijms24087303 - 15 Apr 2023

Cited by 2 | Viewed by 1580

Abstract

Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder caused by loss-of-function mutations in the tumour suppressors TSC1/TSC2, both of which are negative regulators of the mammalian target of rapamycin (mTOR) kinase. Importantly, mTOR hyperactivity seems to be linked [...] Read more.

Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder caused by loss-of-function mutations in the tumour suppressors TSC1/TSC2, both of which are negative regulators of the mammalian target of rapamycin (mTOR) kinase. Importantly, mTOR hyperactivity seems to be linked with the pathobiology of autism spectrum disorders (ASD). Recent studies suggest the potential involvement of microtubule (MT) network dysfunction in the neuropathology of “mTORopathies”, including ASD. Cytoskeletal reorganization could be responsible for neuroplasticity disturbances in ASD individuals. Thus, the aim of this work was to study the effect of Tsc2 haploinsufficiency on the cytoskeletal pathology and disturbances in the proteostasis of the key cytoskeletal proteins in the brain of a TSC mouse model of ASD. Western-blot analysis indicated significant brain-structure-dependent abnormalities in the microtubule-associated protein Tau (MAP-Tau), and reduced MAP1B and neurofilament light (NF-L) protein level in 2-month-old male B6;129S4-Tsc2^tm1Djk/J mice. Alongside, pathological irregularities in the ultrastructure of both MT and neurofilament (NFL) networks as well as swelling of the nerve endings were demonstrated. These changes in the level of key cytoskeletal proteins in the brain of the autistic-like TSC mice suggest the possible molecular mechanisms responsible for neuroplasticity alterations in the ASD brain. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Figure 1

14 pages, 1158 KiB

Open AccessArticle

Relationship between Excreted Uremic Toxins and Degree of Disorder of Children with ASD

by Joško Osredkar, Barbara Žvar Baškovič, Petra Finderle, Barbara Bobrowska-Korczak, Paulina Gątarek, Angelina Rosiak, Joanna Giebułtowicz, Maja Jekovec Vrhovšek and Joanna Kałużna-Czaplińska

Int. J. Mol. Sci. 2023, 24(8), 7078; https://doi.org/10.3390/ijms24087078 - 11 Apr 2023

Cited by 1 | Viewed by 1712

Abstract

Autism spectrum disorder (ASD) is a complex developmental disorder in which communication and behavior are affected. A number of studies have investigated potential biomarkers, including uremic toxins. The aim of our study was to determine uremic toxins in the urine of children with [...] Read more.

Autism spectrum disorder (ASD) is a complex developmental disorder in which communication and behavior are affected. A number of studies have investigated potential biomarkers, including uremic toxins. The aim of our study was to determine uremic toxins in the urine of children with ASD (143) and compare the results with healthy children (48). Uremic toxins were determined with a validated high-performance liquid chromatography coupled to mass spectrometry (LC-MS/MS) method. We observed higher levels of p-cresyl sulphate (pCS) and indoxyl sulphate (IS) in the ASD group compared to the controls. Moreover, the toxin levels of trimethylamine N-oxide (TMAO), symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) were lower in ASD patients. Similarly, for pCS and IS in children classified, according to the intensity of their symptoms, into mild, moderate, and severe, elevated levels of these compounds were observed. For mild severity of the disorder, elevated levels of TMAO and comparable levels of SDMA and ADMA for ASD children as compared to the controls were observed in the urine. For moderate severity of ASD, significantly elevated levels of TMAO but reduced levels of SDMA and ADMA were observed in the urine of ASD children as compared to the controls. When the results obtained for severe ASD severity were considered, reduced levels of TMAO and comparable levels of SDMA and ADMA were observed in ASD children. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Graphical abstract

18 pages, 1310 KiB

Open AccessArticle

Maternal Immune Activation Induced by Prenatal Lipopolysaccharide Exposure Leads to Long-Lasting Autistic-like Social, Cognitive and Immune Alterations in Male Wistar Rats

by Emilia Carbone, Valeria Buzzelli, Antonia Manduca, Stefano Leone, Alessandro Rava and Viviana Trezza

Int. J. Mol. Sci. 2023, 24(4), 3920; https://doi.org/10.3390/ijms24043920 - 15 Feb 2023

Cited by 7 | Viewed by 2254

Abstract

Several studies have supported the association between maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation and an increased susceptibility to the development of various psychiatric and neurological disorders, including autism and other neurodevelopmental disorders (NDDs), [...] Read more.

Several studies have supported the association between maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation and an increased susceptibility to the development of various psychiatric and neurological disorders, including autism and other neurodevelopmental disorders (NDDs), in the offspring. In the present work, we aimed to provide extensive characterization of the short- and long-term consequences of MIA in the offspring, both at the behavioral and immunological level. To this end, we exposed Wistar rat dams to Lipopolysaccharide and tested the infant, adolescent and adult offspring across several behavioral domains relevant to human psychopathological traits. Furthermore, we also measured plasmatic inflammatory markers both at adolescence and adulthood. Our results support the hypothesis of a deleterious impact of MIA on the neurobehavioral development of the offspring: we found deficits in the communicative, social and cognitive domains, together with stereotypic-like behaviors and an altered inflammatory profile at the systemic level. Although the precise mechanisms underlying the role of neuroinflammatory states in neurodevelopment need to be clarified, this study contributes to a better understanding of the impact of MIA on the risk of developing behavioral deficits and psychiatric illness in the offspring. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Figure 1

12 pages, 342 KiB

Open AccessArticle

Serum Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Potential Diagnostic Biomarkers in Autism Spectrum Disorders: A Preliminary Study

by Marta Simone, Andrea De Giacomo, Roberto Palumbi, Claudia Palazzo, Giuseppe Lucisano, Francesco Pompamea, Stefania Micella, Mara Pascali, Alessandra Gabellone, Lucia Marzulli, Paola Giordano, Concetta Domenica Gargano, Lucia Margari, Antonio Frigeri and Maddalena Ruggieri

Int. J. Mol. Sci. 2023, 24(3), 3057; https://doi.org/10.3390/ijms24033057 - 3 Feb 2023

Cited by 6 | Viewed by 2893

Abstract

Autism spectrum disorder (ASD) is one of the most common neurodevelopment disorders, characterized by a multifactorial etiology based on the interaction of genetic and environmental factors. Recent evidence supports the neurobiological hypothesis based on neuroinflammation theory. To date, there are no sufficiently validated [...] Read more.

Autism spectrum disorder (ASD) is one of the most common neurodevelopment disorders, characterized by a multifactorial etiology based on the interaction of genetic and environmental factors. Recent evidence supports the neurobiological hypothesis based on neuroinflammation theory. To date, there are no sufficiently validated diagnostic and prognostic biomarkers for ASD. Therefore, we decided to investigate the potential diagnostic role for ASD of two biomarkers well known for other neurological inflammatory conditions: the glial fibrillary acidic protein (GFAP) and the neurofilament (Nfl). Nfl and GFAP serum levels were analyzed using SiMoA technology in a group of ASD patients and in a healthy control group (CTRS), age- and gender-matched. Then we investigated the distribution, frequency, and correlation between serum Nfl and GFAP levels and clinical data among the ASD group. The comparison of Nfl and GFAP serum levels between ASD children and the control group showed a mean value of these two markers significantly higher in the ASD group (sNfL mean value ASD pt 6.86 pg/mL median value ASD pt 5.7 pg/mL; mean value CTRS 3.55 pg/mL; median value CTRS 3.1 pg; GFAP mean value ASD pt 205.7 pg/mL median value ASD pt 155.4 pg/mL; mean value CTRS 77.12 pg/mL; median value CTRS 63.94 pg/mL). Interestingly, we also found a statistically significant positive correlation between GFAP levels and hyperactivity symptoms (p-value <0.001). Further investigations using larger groups are necessary to confirm our data and to verify in more depth the potential correlation between these biomarkers and ASD clinical features, such as the severity of the core symptoms, the presence of associated symptoms, and/or the evaluation of a therapeutic intervention. However, these data not only might shed a light on the neurobiology of ASD, supporting the neuroinflammation and neurodegeneration hypothesis, but they also might support the use of these biomarkers in the early diagnosis of ASD, to longitudinally monitor the disease activity, and even more as future prognostic biomarkers. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Figure 1

Review

Jump to: Research

26 pages, 1181 KiB

Open AccessReview

Metabolomics: Perspectives on Clinical Employment in Autism Spectrum Disorder

by Martina Siracusano, Lucrezia Arturi, Assia Riccioni, Antonio Noto, Michele Mussap and Luigi Mazzone

Int. J. Mol. Sci. 2023, 24(17), 13404; https://doi.org/10.3390/ijms241713404 - 29 Aug 2023

Cited by 2 | Viewed by 1368

Abstract

Precision medicine is imminent, and metabolomics is one of the main actors on stage. We summarize and discuss the current literature on the clinical application of metabolomic techniques as a possible tool to improve early diagnosis of autism spectrum disorder (ASD), to define [...] Read more.

Precision medicine is imminent, and metabolomics is one of the main actors on stage. We summarize and discuss the current literature on the clinical application of metabolomic techniques as a possible tool to improve early diagnosis of autism spectrum disorder (ASD), to define clinical phenotypes and to identify co-occurring medical conditions. A review of the current literature was carried out after PubMed, Medline and Google Scholar were consulted. A total of 37 articles published in the period 2010–2022 was included. Selected studies involve as a whole 2079 individuals diagnosed with ASD (1625 males, 394 females; mean age of 10, 9 years), 51 with other psychiatric comorbidities (developmental delays), 182 at-risk individuals (siblings, those with genetic conditions) and 1530 healthy controls (TD). Metabolomics, reflecting the interplay between genetics and environment, represents an innovative and promising technique to approach ASD. The metabotype may mirror the clinical heterogeneity of an autistic condition; several metabolites can be expressions of dysregulated metabolic pathways thus liable of leading to clinical profiles. However, the employment of metabolomic analyses in clinical practice is far from being introduced, which means there is a need for further studies for the full transition of metabolomics from clinical research to clinical diagnostic routine. Full article

(This article belongs to the Special Issue From Molecular Mechanism to Therapy in Autism Spectrum Disorder)

► Show Figures

Figure 1

Journal Menu

Journal Browser

From Molecular Mechanism to Therapy in Autism Spectrum Disorder

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Related Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI