Does maternal immune activation lead to neuropsychiatric disorders through altered brain development?

Abstract The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.

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Maternal immune activation causes age-specific changes in cytokine receptor expression in offspring throughout development

10.1101/490466 ◽

2018 ◽

Cited By ~ 2

Author(s):

Myka L. Estes ◽

Bradford M. Elmer ◽

Cameron C. Carter ◽

A. Kimberley McAllister

Keyword(s):

Immune Activation ◽

Synapse Formation ◽

Early Adulthood ◽

Neuropsychiatric Disorders ◽

Receptor Expression ◽

Cytokine Receptor ◽

Cytokine Receptors ◽

Cytokine Signaling ◽

Peak Period ◽

Maternal Immune Activation

Maternal infection is a shared environmental risk factor for a spectrum of neuropsychiatric disorders and animal models of maternal immune activation (MIA) exhibit a range of neuropathologies and behaviors with relevance to these disorders. In particular, MIA offspring show chronic, age- and region-dependent changes in brain cytokines, a feature seen in postmortem studies of individuals with neuropsychiatric disorders. These MIA-induced alterations in brain cytokines may index biological processes underlying progression to diagnosable neuropsychiatric disorders. However, cytokines signal through specific cytokine receptors to alter cellular processes and it is the levels of those receptors that are critical for signaling. Yet, it remains unknown whether MIA alters the expression of cytokine receptors in the brains of offspring throughout postnatal development. Here, we measured the expression of 23 cytokine receptors in the frontal cortex of MIA and control offspring from birth to adulthood using qPCR. MIA offspring show dynamic oscillating alterations in cytokine receptors during sensitive periods of neural growth and synaptogenesis. Of the many cytokine receptors altered in the FC of MIA offspring, five were significantly changed at multiple ages at levels over 2-fold relative to controls (Il1r1, Ifngr1, Il10ra, Cx3cr1 and Gmcsfr), suggesting persistent dysfunction within those pathways. In addition to facilitating immune responses, these cytokine receptors play critical roles in neuronal migration and maturation, synapse formation and elimination, and microglial function. Together with previously reported changes in cytokine levels in the brains of MIA offspring, our results show a decrease in cytokine signaling during the peak period of synaptogenesis and spine formation and an increase during periods of activity-dependent developmentand early adulthood. Overall, the oscillating, age-dependent cytokine receptor alterations in the FC of MIA offspring identified here may have diagnostic and therapeutic value for neuropsychiatric disorders with a neuro-immune etiology.

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Prenatal infection, maternal immune activation, and risk for schizophrenia

Translational Neuroscience ◽

10.2478/s13380-012-0045-6 ◽

2012 ◽

Vol 3 (4) ◽

Cited By ~ 45

Author(s):

Sarah Canetta ◽

Alan Brown

Keyword(s):

Brain Development ◽

Immune Activation ◽

Severe Infection ◽

Epidemiological Studies ◽

Future Research ◽

Preclinical Studies ◽

Preclinical Research ◽

Adult Behavior ◽

Maternal Immune Activation ◽

Prenatal Infection

AbstractA body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed.

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T33. NEUROIMMUNE MECHANISMS OF PSYCHIATRIC DISORDERS: LONGITUDINAL EVALUATION OF DIFFUSION MEASURES OF EXTRACELLULAR FREE WATER IN A NON-HUMAN PRIMATE MODEL OF MATERNAL IMMUNE ACTIVATION

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.593 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S244-S244

Author(s):

Cameron Carter ◽

Tyler Lesh ◽

Ana-Maria Iosef ◽

Costin Tanase ◽

Rosa Vaslova ◽

...

Keyword(s):

White Matter ◽

Brain Development ◽

Psychiatric Disorders ◽

Immune Activation ◽

Free Water ◽

Cingulate Cortex ◽

Synaptic Function ◽

Group Differences ◽

Whole Brain ◽

Maternal Immune Activation

Abstract Background A key finding in developmental neurobiology is a widespread role for immune molecules in normal brain development and synaptic function and evidence has been accumulating for an immune-based developmental pathophysiology in psychiatric disorders, particularly in schizophrenia. Epidemiological studies have revealed an increased incidence of schizophrenia in offspring of mothers who had an infection during pregnancy while GWAS studies have identified genetic links to the major histocompatibility complex and peripheral changes in immune markers are widely reported in the illness. The murine maternal immune activation model system is widely used to investigate the effects of immune activation during pregnancy on brain development in behavior in offspring. Here we report findings from an ongoing study of a unique cohort on non-human primates (NHP) who underwent MIA (compared to controls) on a promising biomarker of neuroimmune perturbation in vivo--extracellular free water--a diffusion magnetic resonance imaging measure obtained with a multi-shell acquisition, which we have shown in multiple studies to be increased in young people with early psychosis. Methods Fourteen pregnant rhesus monkeys (Macaca mulatta) received polyICLC and 14 control animals have been scanned prospectively from both to their current age of 3.5 years. The offspring from both groups underwent a diffusion MRI scan on a 3 Tesla Siemens Skyra scanner in which multiple b-value shells were acquired to improve estimation of extracellular free water. Data were collected when the offspring were 1, 6, 12, 24 and 36 months to date. Diffusion images were nonlinearly aligned to individual subject MPRAGE scans, which were segmented and parcellated into regions of interest using multi-atlas techniques. For this preliminary analysis, frontal, cingulate, and temporo-limbic regions were selected as a priori ROIs in addition to whole-brain gray and white matter masks. Group differences were assessed using repeated measures ANOVA and independent samples t-tests. Results Results from birth to age 2 years showed a significant main effect of group in both white (p<.05) and gray (p<.001) cingulate cortex free water, with MIA-exposed offspring showing higher free water. Similar trends were also identified in prefrontal white matter free water (p=.07) and whole-brain white (p=.11) and gray matter free water (p=.07). No significant group by time interactions were identified. Data analysis is currently underway including the 3-year time point. Discussion Despite the lack of gross behavioral abnormalities at age 2, extracellular free water values are increased in MIA-exposed offspring, particularly in the cingulate cortex. More global whole-brain free water group differences, however, did not reach statistical significance, which may indicate some regional specificity to these changes early in development. These NHP MIA model complement the human schizophrenia literature in which extracellular free water increases have been repeatedly identified. And show that changes in the brain occur early in life, well before the emergence of atypical behaviors in the NHP model.

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Maternal Immune Activation and Neuropsychiatric Disorders: The Intricate Puzzle of Autism Spectrum Disorder

Progress in Inflammation Research - Perinatal Inflammation and Adult Psychopathology ◽

10.1007/978-3-030-39335-9_11 ◽

2020 ◽

pp. 167-205

Author(s):

Mellanie Fontes-Dutra ◽

Bruna Rabelo ◽

Júlio Santos-Terra ◽

Iohanna Deckmann ◽

Gustavo Brum Schwingel ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Immune Activation ◽

Neuropsychiatric Disorders ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Maternal Immune Activation

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Maternal Immune Activation During Pregnancy and Offspring Brain Development

Biological Psychiatry ◽

10.1016/j.biopsych.2021.06.018 ◽

2021 ◽

Vol 90 (5) ◽

pp. 283-285

Author(s):

Claudia Buss

Keyword(s):

Brain Development ◽

Immune Activation ◽

Maternal Immune Activation

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Effect of maternal immune activation on pre‐ and postnatal murine brain development

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.lb32 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Kieran McDermott ◽

Janelle Pakan ◽

Elaine O'Loughlin

Keyword(s):

Brain Development ◽

Immune Activation ◽

Maternal Immune Activation ◽

Murine Brain

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Maternal immune activation: Implications for neuropsychiatric disorders

Science ◽

10.1126/science.aag3194 ◽

2016 ◽

Vol 353 (6301) ◽

pp. 772-777 ◽

Cited By ~ 366

Author(s):

M. L. Estes ◽

A. K. McAllister

Keyword(s):

Immune Activation ◽

Neuropsychiatric Disorders ◽

Maternal Immune Activation

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Lessons From Zika and Other Virus Induced Skull Deformity

FACE ◽

10.1177/2732501620939515 ◽

2020 ◽

Vol 1 (1) ◽

pp. 44-50

Author(s):

Mohamad Masoumy ◽

Emily P. Masoumy ◽

Babak Baban ◽

Jack C. Yu

Keyword(s):

Brain Development ◽

Immune Activation ◽

Viral Infections ◽

Fetal Brain ◽

Growth Dynamics ◽

Cell Loss ◽

Maternal Immune Activation ◽

Skull Deformity ◽

Critical Phases ◽

The Impact

Objective: Viral infections during pregnancy can cause disturbance in normal craniofacial morphogenesis. While some pathogens such as cytomegalovirus and herpes simplex are familiar to us, others remain obscure. This review examines the arbovirus-induced cranial deformities and combines biomechanics with growth dynamics to gain a deeper appreciation of this complex morphogenetic process. Materials and Methods: Using Wolfram Alpha, we analyzed the impact of cell population changes. The growth dynamics of the brain, and thus the size of the calvarium, followed 2 potential logistic curves: compensated and uncompensated. To understand the potential mechanism of cell loss, we performed literature review on maternal immune activation and viral tropism for neurons and glial cells. Results: With arboviral infections such as Zika, uncompensated loss of cells during the critical phases of fetal brain development reduces the intracranial mass and therefore decreases the tensile stress across the cranial sutures. The deflationary effect produces microcephaly by subduction and reduced osteogenesis seen clinically in these infants. Conclusion: Many viral infections cause intense maternal immune activation, some have neurotropism and can result in cell loss within the developing cranium. Unable to overcome this loss, the cranium assumes a new, abnormal shape and volume. Secondary calvarial deformities is due to, and should not cause, changes in brain development.

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