Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Zheng, Zhen; Zhu, Tingting; Qu, Yi; Mu, Dezhi

doi:10.1371/journal.pone.0158688

Cited by 58 publications

(50 citation statements)

References 32 publications

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“…Such cellular changes likely impact on the functional organization of cortical microcircuits in autism, also suggested by molecular studies in animals 4,[22][23][24][25]85,86 . These findings collectively support the imbalance in excitation and inhibition of cortical areas in autism 4,9,16,22,87,88 , which have been related to anomalies in cortical neurotransmitter systems [89][90][91][92] and atypical subcortico-cortical interactions with subcortical structures such as thalamus modulating this balance 7,11,24,74,75,93 . Here, we obtained support for perturbations in cortical microcircuit function from a network perspective, by leveraging a biophysically plausible computational model of brain function, which seeks to tune parameters to optimize the link between structural and connectomes 18 .…”

Section: Discussionsupporting

confidence: 70%

Connectome and microcircuit models implicate atypical subcortico-cortical interactions in autism pathophysiology

Park

Hong

Valk

et al. 2020

Preprint

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Both macroscale connectome miswiring and microcircuit anomalies have been suggested to play a role in the pathophysiology of autism. However, an overarching framework that consolidates these macro and microscale perspectives of the condition is lacking. Here, we combined connectome-wide manifold learning and biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. Our analysis established that autism showed significant differences in structural connectome organization relative to neurotypical controls, with strong effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models revealed that the degree of macroscale anomalies was related to atypical increases of subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic decoding and developmental gene enrichment analyses provided biological context and pointed to genes expressed in cortical and thalamic areas during childhood and adolescence. Supervised machine learning showed the macroscale perturbations predicted sociocognitive symptoms and repetitive behaviors. Our analyses provide convergent support that atypical subcortico-cortical interactions may contribute to both microcircuit and macroscale connectome anomalies in autism.

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Section: Discussionsupporting

confidence: 70%

Connectome and microcircuit models implicate atypical subcortico-cortical interactions in autism pathophysiology

Park

Hong

Valk

et al. 2020

Preprint

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“…Furthermore, we performed oxylipin analysis of blood and brain regions from juvenile offspring. Moreover, we measured levels of N-methyl-D-aspartate receptor (NMDAR)-related amino acids in the blood and brain from juvenile offspring since NMDAR-related amino acids were altered in patients with ASD (33)(34)(35)(36). Third, we performed 16S rRNA analysis and measurement of short-chain fatty acids of fecal samples in juvenile off\spring after maternal glyphosate exposure since abnormal composition of gut microbiota is shown in patients with ASD (36)(37)(38)(39)(40).…”

Section: Significancementioning

confidence: 99%

Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase

Yang

Chang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

117

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Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the precise mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring, and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8 (9)-EpETrE in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.

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“…Changes in the abundance of B. vulgatus were associated with the altered cortisol levels, which may be involved in the pathogenesis of ASD through the HPA pathway . In addition, the abundance of B. vulgatus is significantly positively correlated with the levels of Dglutamine and D-glutamate in the guts of children with ASD [M. Wang et al, 2019] and higher plasma glutamate were found in patients with ASD to in controls [Zheng, Zhu, Qu, & Mu, 2016]. Taken together, this suggests that the elevated levels of B. vulgatus may affect this major excitatory neurotransmitter imbalance and thus contribute to the pathophysiology of ASD.…”

Section: Discussionmentioning

confidence: 96%

Changes in the Gut Microbiota of Children with Autism Spectrum Disorder

et al. 2020

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Alterations in the gut microbiota may influence gastrointestinal (GI) dysbiosis frequently reported in individuals with autism spectrum disorder (ASD). In this study, we sequenced the bacterial 16S rRNA gene to evaluate changes in fecal microbiota between 48 children with ASD and 48 healthy children in China. At the phylum level, the number of Firmicutes, Proteobacteria, and Verrucomicrobia decreased in children with ASD, while the Bacteroidetes/Firmicutes was significantly higher in autistic children due to enrichment of Bacteroidetes. At the genus level, the amount of Bacteroides, Prevotella, Lachnospiracea_incertae_sedis, and Megamonas increased, while Clostridium XlVa, Eisenbergiella, Clostridium IV, Flavonifractor, Escherichia/Shigella, Haemophilus, Akkermansia, and Dialister decreased in children with ASD relative to the controls. Significant increase was observed in the number of species synthesizing branched‐chain amino acids (BCAAs), like Bacteroides vulgatus and Prevotella copri, while the numbers of Bacteroides fragilis and Akkermansia muciniphila decreased in children with ASD compared to the controls. Most importantly, the highest levels of pathogenic bacteria were different for each child with ASD in this cohort. We found that only one functional module, cellular antigens, was enriched in children with ASD, and other pathways like lysine degradation and tryptophan metabolism were significantly decreased in children with ASD. These findings provide further evidence of altered gut microbiota in Chinese ASD children and may contribute to the treatment of patients with ASD. Lay Summary This study characterized the gut bacteria composition of 48 children with ASD and 48 neurotypical children in China. The metabolic disruptions caused by altered gut microbiota may contribute significantly to the neurological pathophysiology of ASD, including significant increases in the number of species synthesizing BCAAs, and decreases in the number of probiotic species. These findings suggest that a gut microbiome‐associated therapeutic intervention may provide a novel strategy for treating GI symptoms frequently seen in individuals with ASD. Autism Res 2020, 13: 1614–1625. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

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Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Cited by 58 publications

References 32 publications

Connectome and microcircuit models implicate atypical subcortico-cortical interactions in autism pathophysiology

Connectome and microcircuit models implicate atypical subcortico-cortical interactions in autism pathophysiology

Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase

Changes in the Gut Microbiota of Children with Autism Spectrum Disorder

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