Controversies and prospects about microglia in maternal immune activation models for neurodevelopmental disorders

Smolders, Silke; Notter, Tina; Smolders, Sophie; Rigo, Jean-Michel; Brône, Bert

doi:10.1016/j.bbi.2018.06.001

Cited by 75 publications

(53 citation statements)

References 152 publications

(261 reference statements)

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“…We previously found that both MIA and microglia embryonic dysfunction modulate the early positioning of interneurons in the developing cortical plate with a subsequent mild increase in the density of PV interneurons in the murine somatosensory cortex (Squarzoni et al, 2014). These findings raise the possibility that prenatal immune challenges, including microglia deficits or MIA, which modifies microglial functioning but also a wide range of additional processes (Estes and McAllister, 2016;Smolders et al, 2018), might interfere with the developmental trajectory of PV interneurons from early stages.…”

Section: Introductionmentioning

confidence: 96%

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

Thion

Mosser

Férézou

et al. 2019

Preprint

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The etiology of neurodevelopmental disorders is linked to defects in Parvalbumin (PV)expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia, have a twostep impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a novel framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring.

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Section: Introductionmentioning

confidence: 96%

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

Thion

Mosser

Férézou

et al. 2019

Preprint

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“…However, failure to replicate these findings indicates that both dose and timing of MIA dictate microglial sensitivity (23). Bacterial lipopolysaccharide (LPS) is also widely used to induce MIA, although disparate effects (on maternal and offspring immune responses and behavior) of TLR-4-activating bacterial endotoxin versus synthetic double-stranded TLR-3 ligand poly I:C have been well documented and create inherent variability in the MIA literature (24)(25)(26). Three consecutive maternal LPS injections increased gene expression of proinflammatory cytokines IL-1β, TNFα, and IL-6 in mouse embryonic microglia (11).…”

mentioning

confidence: 99%

Maternal viral infection causes global alterations in porcine fetal microglia

Antonson

Lawson

Caputo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Maternal infections during pregnancy are associated with increased risk of neurodevelopmental disorders, although the precise mechanisms remain to be elucidated. Previously, we established a maternal immune activation (MIA) model using swine, which results in altered social behaviors of piglet offspring. These behavioral abnormalities occurred in the absence of microglia priming. Thus, we examined fetal microglial activity during prenatal development in response to maternal infection with live porcine reproductive and respiratory syndrome virus. Fetuses were obtained by cesarean sections performed 7 and 21 d postinoculation (dpi). MIA fetuses had reduced brain weights at 21 dpi compared to controls. Furthermore, MIA microglia increased expression of major histocompatibility complex class II that was coupled with reduced phagocytic and chemotactic activity compared to controls. High-throughput gene-expression analysis of microglial-enriched genes involved in neurodevelopment, the microglia sensome, and inflammation revealed differential regulation in primary microglia and in whole amygdala tissue. Microglia density was increased in the fetal amygdala at 7 dpi. Our data also reveal widespread sexual dimorphisms in microglial gene expression and demonstrate that the consequences of MIA are sex dependent. Overall, these results indicate that fetal microglia are significantly altered by maternal viral infection, presenting a potential mechanism through which MIA impacts prenatal brain development and function. maternal immune activation | microglia | neurodevelopment | prenatal inflammation | pig Author contributions: A.M.A., M.A.L., and R.W.J. designed research; A.M.A., M.A.L., M.P.C., S.M.M., and B.J.L. performed research; A.M.A., M.P.C., and S.M.M. analyzed data; A.M.A., M.A.L., and R.W.J. interpreted data; and A.M.A. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission.Published under the PNAS license. NEUROSCIENCEDownloaded by guest on July 10, 2020 3 symbols = P < 0.001, 2 symbols = P < 0.01, and 1 symbol = P < 0.05.Antonson et al.

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“…Maternal immune activation (MIA) in mouse dams in response to a viral mimic, Polyinosinic:polycytidylic acid (Poly IC), at GD 15 decreased microglial phagocytic function and altered behavior consistent with schizophrenia-like traits in humans, changes which were reversed using a partial microglial inhibitor, minocycline [147]. These data point to a potential critical role for microglia in persistent changes in neural function, although other studies have failed to show an impact on microglial function in MIA models [148]. This said, MIA models have typically been limited to infectious stimuli, whereas MIA is likely elicited by a broader range of environmental chemicals or stimuli, and we point to this possibility briefly in the sections that follow.…”

Section: Neuroimmune Responses and Environmental Chemicalsmentioning

confidence: 96%

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

Hollander

Cory‐Slechta

Jacka

et al. 2020

Neuropsychopharmacol.

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The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms-synaptic dysfunction, immune alterations, and gut-brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.

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Controversies and prospects about microglia in maternal immune activation models for neurodevelopmental disorders

Cited by 75 publications

References 152 publications

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

Maternal viral infection causes global alterations in porcine fetal microglia

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

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