scholarly journals Developing Brain Glucose Transporters, Serotonin, Serotonin Transporter, and Oxytocin Receptor Expression in Response to Early-Life Hypocaloric and Hypercaloric Dietary, and Air Pollutant Exposures

2021 ◽  
pp. 1-16
Author(s):  
Xin Ye ◽  
Bo-Chul Shin ◽  
Claire Baldauf ◽  
Amit Ganguly ◽  
Shubhamoy Ghosh ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Prenatal Exposure ◽  
Maternal Diet ◽  
Fetal Brain ◽  
Glucose Transporters ◽  
Autism Spectrum ◽  
Air Pollutant ◽  
Receptor Expression ◽  
Fetal Brain Development ◽  
Spectrum Disorders

Perturbed maternal diet and prenatal exposure to air pollution (AP) affect the fetal brain, predisposing to postnatal neurobehavioral disorders. Glucose transporters (GLUTs) are key in fueling neurotransmission; deficiency of the neuronal isoform GLUT3 culminates in autism spectrum disorders. Along with the different neurotransmitters, serotonin (5-HT) and oxytocin (OXT) are critical for the development of neural connectivity. Serotonin transporter (SERT) modulates synaptic 5-HT levels, while the OXT receptor (OXTR) mediates OXT action. We hypothesized that perturbed brain GLUT1/GLUT3 regulated 5-HT-SERT imbalance, which serves as a contributing factor to postnatal neuropsychiatric phenotypes, with OXT/OXTR providing a counterbalance. Employing maternal diet restriction (intrauterine growth restriction [IUGR]), high-fat (HF) dietary modifications, and prenatal exposure to simulated AP, fetal (E19) murine brain 5-HT was assessed by ELISA with SERT and OXTR being localized by immunohistochemistry and measured by quantitative Western blot analysis. IUGR with lower head weights led to a 48% reduction in male and female fetal brain GLUT3 with no change in GLUT1, when compared to age- and sex-matched controls, with no significant change in OXTR. In addition, a ∼50% (<i>p</i> = 0.005) decrease in 5-HT and SERT concentrations was displayed in fetal IUGR brains. In contrast, despite emergence of microcephaly, exposure to a maternal HF diet or AP caused no significant changes. We conclude that in the IUGR during fetal brain development, reduced GLUT3 is associated with an imbalanced 5-HT-SERT axis. We speculate that these early changes may set the stage for altering the 5HT-SERT neural axis with postnatal emergence of associated neurodevelopmental disorders.

scholarly journals Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

2021 ◽  
Author(s):  
Benjamin I Laufer ◽  
Kari E Neier ◽  
Anthony E Valenzuela ◽  
Dag H Yasui ◽  
Rebecca J Schmidt ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Polychlorinated Biphenyls ◽  
Prenatal Exposure ◽  
Neurodevelopmental Disorder ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Cellular Adhesion ◽  
Genome Wide ◽  
Genome Bisulfite Sequencing ◽  
Spectrum Disorders

Background: Polychlorinated biphenyls (PCBs) are developmental neurotoxicants implicated as environmental risk factors for neurodevelopmental disorders (NDD), including autism spectrum disorders (ASD). Objective: We examined the effects of prenatal exposure to a human-relevant mixture of PCBs on the DNA methylome of fetal mouse brain and placenta to determine if there was a shared subset of differentially methylated regions (DMRs). Methods: A PCB mixture formulated to model the 12 most abundant congeners detected in the serum of pregnant women from a prospective high-risk ASD cohort was administered to female mice prior to and during pregnancy. Whole-genome bisulfite sequencing (WGBS) was performed to assess genome-wide DNA methylation profiles of placenta and brain on gestational day 18. Results: We found thousands of significant (empirical p < 0.05) DMRs distinguishing placentas and brains from PCB-exposed embryos from sex-matched vehicle controls. In both placenta and brain, PCB-associated DMRs were significantly (p < 0.005) enriched for functions related to neurodevelopment, cellular adhesion, and cellular signaling, and significantly (Odds Ratio > 2.4, q < 0.003) enriched for bivalent chromatin marks. The placenta and brain PCB DMRs overlapped significantly (Z-score = 4.5, p = 0.0001) by genomic coordinate and mapped to a shared subset of genes significantly (q < 0.05) enriched for Wnt signaling, Slit/Robo signaling, and genes differentially expressed in multiple NDD/ASD models. The placenta and brain DMRs also significantly (q < 0.05) overlapped by genomic coordinate with brain samples from humans with Rett syndrome and Dup15q syndrome. Discussion: These results demonstrate that placenta can be used as a surrogate for embryonic brain DNA methylation changes over genes relevant to NDD/ASD in a mouse model of prenatal PCB exposure.

scholarly journals CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexis Papariello ◽  
David Taylor ◽  
Ken Soderstrom ◽  
Karen Litwa
Keyword(s):  
Brain Development ◽  
Spontaneous Activity ◽  
Microelectrode Array ◽  
Cannabinoid Receptor ◽  
Fetal Brain ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

Gluten Intolerance and Neurodevelopmental Disorders: Is Nitric Oxide the Common Biomarker Linking These Conditions?

2016 ◽  
Vol 69 (1) ◽  
pp. 54-55 ◽  
Author(s):  
Keith Fluegge
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Air Pollutant ◽  
Clinical Feature ◽  
Nutrient Deficiencies ◽  
Hyperactivity Disorder ◽  
Spectrum Disorders ◽  
The Relationship

Cruchet et al. attempt to tease out the myths and facts surrounding the growing popularity of certain dietary approaches in the management of neurodevelopmental disorders, like attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs). The authors identify a particular exclusionary-type approach that seeks to eliminate dietary gluten. Although the relationship between celiac disease (CD) and ADHD/ASD is not well established, a repeated clinical feature noted in CD is the elevated levels of nitric oxide in serum and urine. Elevated oxidative stress has also been observed in neurodevelopmental conditions, and the author of this correspondence has been the first to propose that chronic, environmental exposure to the air pollutant, nitrous oxide may contribute to these oxidative stress profiles through neural cholinergic perturbation. Therefore, the purpose of this correspondence is to highlight this biochemical connection between these conditions so as to identify the clinical populations who may realize the greatest benefit of these dietary approaches, while minimizing any potential risk of nutrient deficiencies.

scholarly journals Thiamin deficiency on fetal brain development with and without prenatal alcohol exposure

2018 ◽  
Vol 96 (2) ◽  
pp. 169-177 ◽  
Author(s):  
Olena Kloss ◽  
N.A. Michael Eskin ◽  
Miyoung Suh
Keyword(s):  
Brain Development ◽  
Prenatal Exposure ◽  
Prenatal Alcohol Exposure ◽  
Fetal Brain ◽  
Alcohol Exposure ◽  
Brain Dysfunction ◽  
Negative Effects ◽  
Thiamin Deficiency ◽  
Optimal Health ◽  
Fetal Brain Development

Adequate thiamin levels are crucial for optimal health through maintenance of homeostasis and viability of metabolic enzymes, which require thiamine as a co-factor. Thiamin deficiency occurs during pregnancy when the dietary intake is inadequate or excessive alcohol is consumed. Thiamin deficiency leads to brain dysfunction because thiamin is involved in the synthesis of myelin and neurotransmitters (e.g., acetylcholine, γ-aminobutyric acid, glutamate), and its deficiency increases oxidative stress by decreasing the production of reducing agents. Thiamin deficiency also leads to neural membrane dysfunction, because thiamin is a structural component of mitochondrial and synaptosomal membranes. Similarly, in-utero exposure to alcohol leads to fetal brain dysfunction, resulting in negative effects such as fetal alcohol spectrum disorder (FASD). Thiamin deficiency and prenatal exposure to alcohol could act synergistically to produce negative effects on fetal development; however, this area of research is currently under-studied. This minireview summarizes the evidence for the potential role of thiamin deficiency in fetal brain development, with or without prenatal exposure to alcohol. Such evidence may influence the development of new nutritional strategies for preventing or mitigating the symptoms of FASD.

scholarly journals A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

2018 ◽  
Author(s):  
Vahid H. Gazestani ◽  
Tiziano Pramparo ◽  
Srinivasa Nalabolu ◽  
Benjamin P. Kellman ◽  
Sarah Murray ◽  
...  
Keyword(s):  
Brain Development ◽  
Gene Network ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Typical Development ◽  
Core Network ◽  
Neuron Models ◽  
Risk Genes ◽  
Fetal Brain Development ◽  
Upstream Regulators

ABSTRACTHundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1-4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.

The 5-HTTLPR polymorphism of the serotonin transporter gene and child's sex moderate the relationship between disaster-related prenatal maternal stress and autism spectrum disorder traits: The QF2011 Queensland flood study

2018 ◽  
Vol 31 (04) ◽  
pp. 1395-1409 ◽  
Author(s):  
David P. Laplante ◽  
Gabrielle Simcock ◽  
Lei Cao-Lei ◽  
Maya Mouallem ◽  
Guillaume Elgbeili ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Rating Scales ◽  
Maternal Stress ◽  
Short Form ◽  
Autism Spectrum ◽  
Prenatal Maternal Stress ◽  
Peritraumatic Dissociation ◽  
Two Factors ◽  
Spectrum Disorders ◽  
The Relationship

AbstractThe 5-HTTLPR polymorphism of the serotonin transporter has been shown to play a role in autism spectrum disorders (ASD). Moreover, disaster-related prenatal maternal stress (PNMS) has also been shown to be associated with ASD. However, no study to date has examined whether these two factors, either individually or in combination, are predictive of ASD traits in the same sample. We hypothesized that children, particularly boys, with the LL genotype exposed to high levels of disaster-related PNMS would exhibit higher levels of ASD traits compared to boys with the LS or SS genotypes and girls regardless of genotype. Genotype and ASD levels obtained using the Australian normed Autism Spectrum Rating Scales – Short Form were available for 105 30-month-old children exposed to varying levels of PNMS following the 2011 Queensland Flood. For boys, higher ASD traits were associated with the 5-HTTLPR LL genotype in combination with either a negative maternal appraisal of the flood, or high levels of maternal composite subjective stress, PSTD-like or peritraumatic dissociation symptoms. For girls, maternal peritraumatic dissociation levels in combination with the 5-HTTLPR LS or SS genotype were associated with higher ASD traits. The present findings are the first to demonstrate that children’s genotype moderates effects of disaster-related PNMS on ASD traits, with different pattern according to child sex.

Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring

2017 ◽  
Vol 26 (7) ◽  
pp. 812-818 ◽  
Author(s):  
XiuJuan Su ◽  
Wei Yuan ◽  
JianPing Chen ◽  
MaoHua Miao ◽  
Jørn Olsen ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Prenatal Exposure ◽  
Autism Spectrum ◽  
Spectrum Disorders

scholarly journals Mycobacterium tuberculosis-Induced Maternal Immune Activation Promotes Autism-Like Phenotype in Infected Mice Offspring

2021 ◽  
Vol 18 (9) ◽  
pp. 4513
Author(s):  
Wadzanai Manjeese ◽  
Nontobeko E. Mvubu ◽  
Adrie J. C. Steyn ◽  
Thabisile Mpofana
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Activation ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Necrosis Factor Alpha ◽  
Altered Expression ◽  
Maternal Immune Activation ◽  
Persistent Inflammation ◽  
Cytokine Levels ◽  
Fetal Brain Development

The maternal system’s exposure to pathogens during pregnancy influences fetal brain development causing a persistent inflammation characterized by elevated pro-inflammatory cytokine levels in offspring. Mycobacterium tuberculosis (Mtb) is a global pathogen that causes tuberculosis, a pandemic responsible for health and economic burdens. Although it is known that maternal infections increase the risk of autism spectrum disorder (ASD), it is not known whether Mtb infection is sufficient to induce ASD associated behaviors, immune dysregulation and altered expression of synaptic regulatory genes. The current study infected pregnant Balb/c mice with Mtb H37Rv and valproic acid (VPA) individually and in combination. Plasma cytokine profiles were measured in offspring using the Bio-plex Th17 pro mouse cytokine panel. Mtb infection increased plasma interleukin (IL)-6 and IL-17A, while tumor necrosis factor alpha (TNF-α), interferon (IFN)-γ and IL-1β were reduced when compared with saline. Mtb-induced maternal immune activation (MIA) offspring displayed increased grooming behavior. The study also revealed dysregulation in gene expression of synaptic molecules in the cerebellum. MIA rescued the VPA-induced effects on self-grooming and social interaction behaviors. Our finding therefore highlights a potential role of Mtb as a MIA agent that can potentially contribute to ASD.

scholarly journals Role of the Immune System in Autism Spectrum Disorders (ASD)

2018 ◽  
Vol 17 (7) ◽  
pp. 489-495 ◽  
Author(s):  
Heidi Ormstad ◽  
Vesna Bryn ◽  
Ola Didrik Saugstad ◽  
Ola Skjeldal ◽  
Michael Maes
Keyword(s):  
Autism Spectrum Disorders ◽  
Nitrosative Stress ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Future Research ◽  
Children With Asd ◽  
Selective Review ◽  
Immunological Mechanisms ◽  
Increased Risk ◽  
Spectrum Disorders

Background: The evidence based supports that multifactorial and complex immune interactions play a role in autism spectrum disorders (ASD), but contradictory findings are also reported. Objective: The aim of this selective review was to identify trends in the research literature on this topic, focusing on immunology and other aberrations with respect to the different ASD subtypes. Methods: This selective review is based on original and review articles written in English and identified in literature searches of PubMed. Results: Several studies have found that the risk of ASD is greater among children whose mothers suffered from autoimmune diseases while pregnant. Moreover, individuals with ASD show increased levels of antibodies that are specific for several specific proteins. Studies also show that mothers of children with ASD have antibodies against fetal brain proteins. There are also reports on the associations between increased levels of proinflammatory cytokines and ASD. Finally, infections in mothers during pregnancy are linked to an increased risk of ASD. Conclusion: We propose that the large inconsistencies in findings among studies in the field are due to differences in subdiagnoses among the included children with ASD. Well-phenotyped ASD samples are needed to understand the biological and immunological mechanisms underpinning ASD and its subdiagnoses. Future research should apply new strategies to scrutinize the link between ASD and changes in immune responsivity. Important new research avenues are to investigate the associations (a) between different ASD phenotypes and aberrations in (auto)immune pathways and (b) between reduced natural regulatory autoimmune responses during pregnancy, which are in turn associated with increased oxidative and nitrosative stress in maternal blood and putative detrimental effects in the offspring.

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