Maternal immune activation evoked by polyinosinic:polycytidylic acid does not evoke microglial cell activation in the embryo

Smolders, Silke; Smolders, Sophie; Nina, S.; Gartner, Agnès; Rigo, Jean-Michel; Legendre, Pascal; Brône, Bert

doi:10.3389/fncel.2015.00301

Cited by 56 publications

(65 citation statements)

References 69 publications

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“…In our model, an indication of excessive neural progenitor cell phagocytosis was evident in the decreased estimated hippocampal neuronal cell density in MIA piglets, while microglial overactivation (measured by MHCII expression) was not apparent. A lack of microglial activation aligns with previous studies [30, 79-81], though we acknowledge that lasting microglial activation in this model cannot be ruled out solely by MHCII expression. Though MHCII is a widely used marker of classic microglial activation, microglia continuously take on varying states of activation that do not necessarily fall into classic or alternative categorizations [82-84] and resting or quiescent microglia still actively survey their environment and can engulf and clear parenchymal debris [85].…”

Section: Discussionsupporting

confidence: 65%

“…Microglia begin colonizing the brain during early gestation [24, 25] and aid in healthy neurodevelopment by producing neurotrophic factors and by phagocytosing excess cells and synapses [24-29]. Currently, studies determining the role of fetal microglia in MIA are conflicting; though Cunningham et al [24] demonstrated that activated microglia in a maternal LPS model deplete the fetal neural progenitor pool by excessive phagocytosis, Smolders et al [30] failed to find any activation of fetal microglia due to maternal poly I:C treatment at embryonic day (E) 11.5 or double injection at E11.5 and E15.5. Pratt et al [31], however, demonstrated that the same dose of poly I:C administered at E12.5 resulted in an increased production of several proinflammatory cytokines and chemokines by fetal microglia, while the total number of microglia was unchanged.…”

Section: Introductionmentioning

confidence: 99%

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Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

et al. 2018

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Maternal infection during pregnancy increases the risk of neurobehavioral problems in offspring. Evidence from rodent models indicates that the maternal immune response to infection can alter fetal brain development, particularly in the hippocampus. However, information on the effects of maternal viral infection on fetal brain development in gyrencephalic species is limited. Thus, the objective of this study was to assess several effects of maternal viral infection in the last one-third of gestation on hippocampal gene expression and development in fetal piglets. Pregnant gilts were inoculated with porcine reproductive and respiratory syndrome virus (PRRSV) at gestational day (GD) 76 and the fetuses were removed by cesarean section at GD 111 (3 days before anticipated parturition). The gilts infected with PRRSV had elevated plasma interleukin-6 levels and developed transient febrile and anorectic responses lasting approximately 21 days. Despite having a similar overall body weight, fetuses from the PRRSV-infected gilts had a decreased brain weight and altered hippocampal gene expression compared to fetuses from control gilts. Notably, maternal infection caused a reduction in estimated neuronal numbers in the fetal dentate gyrus and subiculum. The number of proliferative Ki-67+ cells was not altered, but the relative integrated density of GFAP+ staining was increased, in addition to an increase in GFAP gene expression, indicating astrocyte-specific gliosis. Maternal viral infection caused an increase in fetal hippocampal gene expression of the inflammatory cytokines TNF-α and IFN-γ and the myelination marker myelin basic protein. MHCII protein, a classic monocyte activation marker, was reduced in microglia, while expression of the MHCII gene was decreased in hippocampal tissue of the fetuses from PRRSV-infected gilts. Together, these data suggest that maternal viral infection at the beginning of the last trimester results in a reduction in fetal hippocampal neurons that is evident 5 weeks after infection, when fetal piglets are near full term. The neuronal reduction was not accompanied by pronounced neuroinflammation at GD 111, indicating that any activation of classic neuroinflammatory pathways by maternal viral infection, if present, is mostly resolved by parturition.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

et al. 2018

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“…While these data suggest that some aspect of microglia respond in a lasting way to early-life insult, the literature is mixed with regard to the longevity and magnitude of these changes (Smolders et al, 2015; Antonson et al, 2016; Giovanoli et al, 2016). Additionally, there are only a few studies that address how embryonic microglia morphology reflects their function.…”

Section: Discussionmentioning

confidence: 99%

The role of IL-6 in neurodevelopment after prenatal stress

Gumusoglu

Fine

Murray

et al. 2017

Brain, Behavior, and Immunity

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Prenatal stress exposure is associated with adverse psychiatric outcomes, including autism and ADHD, as well as locomotor and social inhibition and anxiety-like behaviors in animal offspring. Similarly, maternal immune activation also contributes to psychiatric risk and aberrant offspring behavior. The mechanisms underlying these outcomes are not clear. Offspring microglia and the pro-inflammatory cytokine interleukin-6 (IL-6), known to influence microglia, may serve as common mechanisms between prenatal stress and prenatal immune activation. To evaluate the role of prenatal IL-6 in prenatal stress, microglia morphological analyses were conducted at embryonic days 14 (E14), E15, and in adult mice. Offspring microglia and behavior were evaluated after repetitive maternal restraint stress, repetitive maternal IL-6, or maternal IL-6 blockade during stress from E12 onwards. At E14, novel changes in cortical plate embryonic microglia were documented—a greater density of the mutivacuolated morphology. This resulted from either prenatal stress or IL-6 exposure and was prevented by IL-6 blockade during prenatal stress. Prenatal stress also resulted in increased microglia ramification in adult brain, as has been previously shown. As with embryonic microglia, prenatal IL-6 recapitulated prenatal stress-induced changes in adult microglia. Furthermore, prenatal IL-6 was able to recapitulate the delay in GABAergic progenitor migration caused by prenatal stress. However, IL-6 mechanisms were not necessary for this delay which persisted after prenatal stress despite IL-6 blockade. As we have previously demonstrated, behavioral effects of prenatal stress in offspring, including increased anxiety-like behavior, decreased sociability, and locomotor inhibition, may be related to these GABAergic delays. While adult microglia changes were ameliorated by IL-6 blockade, these behavioral changes were independent of IL-6 mechanisms, similar to GABAergic delays. This and previous work from our laboratory suggest multiple mechanisms, including GABAergic delays, may underlie prenatal stress-linked deficits.

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“…Interestingly, a recent study using the same poly(I:C)--based immune activation model in mice showed that there were no significant differences in fetal microglial cell density or activation levels between offspring of immune--stimulated and control mothers (Smolders et al, 2015). Our interpretations are consistent with these findings and generally question a major involvement of microglia--driven processes in precipitating short--and long--term The line plot shows percent prepulse inhibition (%PPI) as a function of the 3 distinct pulse levels (P--100, P--110 and P--120, which correspond to 100, 110 and 120 dBA) and prepulse levels (+6, +12 and +18 dBA above background of 65 dBA) for pubescent and adult offspring of poly(I:C)--exposed (POL) and control (CON) mothers, and the bar plot depicts the mean %PPI across all prepulse and pulse stimuli used.…”

mentioning

confidence: 98%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

124

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Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre-and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1 levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. AbstractPrenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre--and postsynaptic deficits.Using a well--established mouse model of maternal exposure to the viral mimetic polyriboinosinic--polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)--exposed and control mothers. We found that prenatal immune activation induced adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early--life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial a...

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Maternal immune activation evoked by polyinosinic:polycytidylic acid does not evoke microglial cell activation in the embryo

Cited by 56 publications

References 69 publications

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

The role of IL-6 in neurodevelopment after prenatal stress

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

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