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

Giovanoli, Sandra; Weber‐Stadlbauer, Ulrike; Schedlowski, Manfred; Meyer, Urs; Engler, Harald

doi:10.1016/j.bbi.2015.09.015

Cited by 124 publications

(103 citation statements)

References 128 publications

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“…These include enzymes like MMPs (matrix metalloproteinases) and ADAMTSs (a disintegrin and metalloproteinase with a thrombospondin motif). However, we observed no signs of changes in microglial density or gross morphology, consistent with other studies that examined microglia after prenatal polyI:C treatment7576. The lack of ongoing inflammatory processes suggests that the effects we observed are the consequence of disturbed developmental trajectories rather than ongoing immune dysfunction as a result of prenatal infection.…”

Section: Discussionsupporting

confidence: 90%

Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

Paylor

Lins

Greba

et al. 2016

Sci Rep

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Maternal infection during pregnancy increases the risk of offspring developing schizophrenia later in life. Similarly, animal models of maternal immune activation (MIA) induce behavioural and anatomical disturbances consistent with a schizophrenia-like phenotype in offspring. Notably, cognitive impairments in tasks dependent on the prefrontal cortex (PFC) are observed in humans with schizophrenia and in offspring after MIA during pregnancy. Recent studies of post-mortem tissue from individuals with schizophrenia revealed deficits in extracellular matrix structures called perineuronal nets (PNNs), particularly in PFC. Given these findings, we examined PNNs over the course of development in a well-characterized rat model of MIA using polyinosinic-polycytidylic acid (polyI:C). We found selective reductions of PNNs in the PFC of polyI:C offspring which did not manifest until early adulthood. These deficits were not associated with changes in parvalbumin cell density, but a decrease in the percentage of parvalbumin cells surrounded by a PNN. Developmental expression of PNNs was also significantly altered in the amygdala of polyI:C offspring. Our results indicate MIA causes region specific developmental abnormalities in PNNs in the PFC of offspring. These findings confirm the polyI:C model replicates neuropathological alterations associated with schizophrenia and may identify novel mechanisms for cognitive and emotional dysfunction in the disorder.

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Section: Discussionsupporting

confidence: 90%

Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

Paylor

Lins

Greba

et al. 2016

Sci Rep

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“…S8, E and F), suggesting the overall expression program of poly I:C mice was realigned with the normal phenotype at adulthood. This may explain why previous studies of adult microglia in MIA did not uncover microglia perturbations (66), and emphasizes that a transient perturbation in microglia development might have far reaching implications on the brain in adulthood. Overall, microglia from mice subjected to MIA and analyzed at the pre-microglia stage were transcriptionally shifted toward a more advanced developmental stage.…”

Section: Microglia Development Is Perturbed By Immune Activation Durimentioning

confidence: 89%

Microglia development follows a stepwise program to regulate brain homeostasis

Matcovitch-Natan

Winter

Giladi

et al. 2016

Science

961

1,005

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Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

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

Cited by 124 publications

References 128 publications

Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

Microglia development follows a stepwise program to regulate brain homeostasis

The role of IL-6 in neurodevelopment after prenatal stress

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