scholarly journals Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

2017 ◽  
Vol 23 (4) ◽  
pp. 1001-1013 ◽  
Author(s):  
M V Lombardo ◽  
H M Moon ◽  
J Su ◽  
T D Palmer ◽  
E Courchesne ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Immune Activation ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Maternal Immune Activation ◽  
Brain Transcriptome

scholarly journals Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder

PLoS ONE ◽  
2017 ◽  
Vol 12 (2) ◽  
pp. e0171643 ◽  
Author(s):  
David N. Ruskin ◽  
Michelle I. Murphy ◽  
Sierra L. Slade ◽  
Susan A. Masino
Keyword(s):  
Autism Spectrum Disorder ◽  
Ketogenic Diet ◽  
Immune Activation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Activation Model ◽  
Maternal Immune Activation

scholarly journals Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

2016 ◽  
Author(s):  
Michael V. Lombardo ◽  
Hyang Mi Moon ◽  
Jennifer Su ◽  
Theo D. Palmer ◽  
Eric Courchesne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Autism Spectrum Disorder ◽  
Translation Initiation ◽  
Immune Activation ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Brain Gene Expression ◽  
Maternal Immune Activation ◽  
Increased Risk

AbstractMaternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates fetal brain gene expression near the end of the first trimester of human gestation in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in ASD cortex later in life and which are canonically known for roles in affecting prenatally-late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage, and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e-axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

scholarly journals Interaction between Maternal Immune Activation and Antibiotic Use during Pregnancy and Child Risk of Autism Spectrum Disorder

2020 ◽  
Vol 13 (12) ◽  
pp. 2230-2241 ◽  
Author(s):  
Calliope Holingue ◽  
Martha Brucato ◽  
Christine Ladd‐Acosta ◽  
Xiumei Hong ◽  
Heather Volk ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Immune Activation ◽  
Antibiotic Use ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Maternal Immune Activation

scholarly journals Metabolic and behavioral features of acute hyperpurinergia and the maternal immune activation mouse model of autism spectrum disorder

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248771
Author(s):  
Zarazuela Zolkipli-Cunningham ◽  
Jane C. Naviaux ◽  
Tomohiro Nakayama ◽  
Charlotte M. Hirsch ◽  
Jonathan M. Monk ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Immune Activation ◽  
Purinergic Signaling ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Whole Body ◽  
Systemic Injection ◽  
Maternal Immune Activation ◽  
Behavioral Features ◽  
Rebound Increase

Since 2012, studies in mice, rats, and humans have suggested that abnormalities in purinergic signaling may be a final common pathway for many genetic and environmental causes of autism spectrum disorder (ASD). The current study in mice was conducted to characterize the bioenergetic, metabolomic, breathomic, and behavioral features of acute hyperpurinergia triggered by systemic injection of the purinergic agonist and danger signal, extracellular ATP (eATP). Responses were studied in C57BL/6J mice in the maternal immune activation (MIA) model and controls. Basal metabolic rates and locomotor activity were measured in CLAMS cages. Plasma metabolomics measured 401 metabolites. Breathomics measured 98 volatile organic compounds. Intraperitoneal eATP dropped basal metabolic rate measured by whole body oxygen consumption by 74% ± 6% (mean ± SEM) and rectal temperature by 6.2˚ ± 0.3˚C in 30 minutes. Over 200 metabolites from 37 different biochemical pathways where changed. Breathomics showed an increase in exhaled carbon monoxide, dimethylsulfide, and isoprene. Metabolomics revealed an acute increase in lactate, citrate, purines, urea, dopamine, eicosanoids, microbiome metabolites, oxidized glutathione, thiamine, niacinamide, and pyridoxic acid, and decreased folate-methylation-1-carbon intermediates, amino acids, short and medium chain acyl-carnitines, phospholipids, ceramides, sphingomyelins, cholesterol, bile acids, and vitamin D similar to some children with ASD. MIA animals were hypersensitive to postnatal exposure to eATP or poly(IC), which produced a rebound increase in body temperature that lasted several weeks before returning to baseline. Acute hyperpurinergia produced metabolic and behavioral changes in mice. The behaviors and metabolic changes produced by ATP injection were associated with mitochondrial functional changes that were profound but reversible.

scholarly journals Maternal iodine status in a multi-ethnic UK birth cohort: associations with autism spectrum disorder

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kirsten Jade Cromie ◽  
Diane Erin Threapleton ◽  
Charles Jonathan Peter Snart ◽  
Elizabeth Taylor ◽  
Dan Mason ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Thyroid Hormones ◽  
Iodine Deficiency ◽  
Urinary Iodine ◽  
Fetal Brain ◽  
First Trimester ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Iodine Status ◽  
Increased Risk

Abstract Background Maternal iodine requirements increase during pregnancy to supply thyroid hormones essential for fetal brain development. Maternal iodine deficiency can lead to hypothyroxinemia, a reduced fetal supply of thyroid hormones which, in the first trimester, has been linked to an increased risk of autism spectrum disorder (ASD) in the child. No study to date has explored the direct link between maternal iodine deficiency and diagnosis of ASD in offspring. Methods Urinary iodine concentrations (UIC) and iodine/creatinine ratios (I:Cr) were measured in 6955 mothers at 26–28 weeks gestation participating in the Born in Bradford (BiB) cohort. Maternal iodine status was examined in relation to the probability of a Read (CTV3) code for autism being present in a child’s primary care records through a series of logistic regression models with restricted cubic splines. Results Median (inter-quartile range) UIC was 76 μg/L (46, 120) and I:Cr was 83 μg/g (59, 121) indicating a deficient population according to WHO guidelines. Ninety two children (1·3%) in our cohort had received a diagnosis of ASD by the census date. Overall, there was no evidence to support an association between I:Cr or UIC and ASD risk in children aged 8–12 years (p = 0·3). Conclusions There was no evidence of an increased clinical ASD risk in children born to mothers with mild-to-moderate iodine deficiency at 26 weeks gestation. Alternative functional biomarkers of exposure and a wider range of conditions may provide further insight.

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