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 Maternal immune activation induces sustained changes in fetal microglia motility

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kana Ozaki ◽  
Daisuke Kato ◽  
Ako Ikegami ◽  
Akari Hashimoto ◽  
Shouta Sugio ◽  
...  
Keyword(s):  
Immune Activation ◽  
Immune Status ◽  
Developmental Stages ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Behavioral Deficits ◽  
Maternal Immune Activation ◽  
Cytokine Levels ◽  
Spectrum Disorders ◽  
Increased Susceptibility

AbstractMaternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.

scholarly journals Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

2007 ◽  
Vol 27 (40) ◽  
pp. 10695-10702 ◽  
Author(s):  
S. E. P. Smith ◽  
J. Li ◽  
K. Garbett ◽  
K. Mirnics ◽  
P. H. Patterson
Keyword(s):  
Brain Development ◽  
Immune Activation ◽  
Interleukin 6 ◽  
Fetal Brain ◽  
Maternal Immune Activation ◽  
Fetal Brain Development

scholarly journals Fetal innate immunity contributes to the induction of atypical behaviors in a mouse model of maternal immune activation

2020 ◽  
Author(s):  
Eva K. Nichols ◽  
Hsiu-Chun Chuang ◽  
Matthew T. Davis ◽  
Kristina M. Geiger ◽  
Rick Z. Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Activation ◽  
Repetitive Behavior ◽  
Fetal Brain ◽  
Toll Like Receptor ◽  
Neurodevelopmental Outcomes ◽  
Behavioral Phenotypes ◽  
Maternal Immune Activation ◽  
Fetal Brain Development ◽  
Adapter Molecule

SummaryMaternal immune activation (MIA) increases likelihood of altered neurodevelopmental outcomes. Maternal cytokines are proposed to affect fetal brain development in mice; however, the contribution of fetal immunity to neurodevelopmental disorders is largely unexplored. Here, we show that MIA mediated by Toll-like receptor 3 (TLR3), but not other TLRs, induces a specific set of behavioral phenotypes including decreased sociability and increased restricted repetitive behavior in offspring. Accordingly, these behavioral phenotypes were absent when offspring were deficient for Trif, the downstream adapter molecule of TLR3. Using single-cell RNA sequencing, we identified clusters of border-associated macrophages that were significantly enriched in the fetal brain following TLR3-MIA, and these clusters were diminished in Trif−/− fetal brains.Moreover, we found that triggering TLR3-TRIF in offspring can occur through transplacental viral infection, resulting in altered behavioral phenotypes. Collectively, our data indicate that fetal innate immunity contributes to MIA-induced atypical behaviors in mice.

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 Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats

2020 ◽  
Vol 11 ◽  
Author(s):  
Kelly J. Baines ◽  
Dendra M. Hillier ◽  
Faraj L. Haddad ◽  
Nagalingam Rajakumar ◽  
Susanne Schmid ◽  
...  
Keyword(s):  
Brain Development ◽  
Immune Activation ◽  
Fetal Brain ◽  
Precursor Cells ◽  
Neural Precursor Cells ◽  
Neural Precursor ◽  
Maternal Immune Activation ◽  
Fetal Brain Development

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.

scholarly journals The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

2021 ◽  
Vol 11 (3) ◽  
pp. 344
Author(s):  
Kinga Gzielo ◽  
Agnieszka Potasiewicz ◽  
Ewa Litwa ◽  
Diana Piotrowska ◽  
Piotr Popik ◽  
...  
Keyword(s):  
Immune Activation ◽  
Social Play ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Rats ◽  
Poly I:C ◽  
Maternal Immune Activation ◽  
Increased Risk ◽  
Adolescent Rats ◽  
The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

Maternal Immune Activation in the Rat Alters Maternofetal Leucine Transport and Fetal Brain Growth

Placenta ◽  
2021 ◽  
Vol 112 ◽  
pp. e13
Author(s):  
Hager M. Kowash ◽  
Harry G. Potter ◽  
Nick Ashton ◽  
Reinmar Hager ◽  
Joanna C. Neill ◽  
...  
Keyword(s):  
Immune Activation ◽  
Fetal Brain ◽  
Brain Growth ◽  
Maternal Immune Activation ◽  
Leucine Transport
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