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Cited by 146Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchTryptophan and brain disorders

Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function

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Roumier, Anne, Pascual, Olivier, Béchade, Catherine, Wakselman, Shirley, Poncer, Jean-Christophe, Réal, Eleonore, Triller, Antoine, Bessis, Alain·2008·PLoS ONE
DOI 10.1371/journal.pone.0002595PMC PMC2440505
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Abstract

BACKGROUND: Epidemiological studies have linked maternal infection during pregnancy to later development of neuropsychiatric disorders in the offspring. In mice, experimental inflammation during embryonic development impairs behavioral and cognitive performances in adulthood. Synaptic dysfunctions may be at the origin of cognitive impairments, however the link between prenatal inflammation and synaptic defects remains to be established. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that prenatal alteration of microglial function, including inflammation, induces delayed synaptic dysfunction in the adult. DAP12 is a microglial signaling protein expressed around birth, mutations of which in the human induces the Nasu-Hakola disease, characterized by early dementia. We presently report that synaptic excitatory currents in mice bearing a loss-of-function mutation in the DAP12 gene (DAP12(KI) mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12(KI) P0 pups cultured without microglia develop similar synaptic alterations, suggesting that a prenatal dysfunction of microglia may impact synaptic function in the adult. As we observed that DAP12(KI) microglia overexpress genes for IL1beta, IL6 and NOS2, which are inflammatory proteins, we analyzed the impact of a pharmacologically-induced prenatal inflammation on synaptic function. Maternal injection of lipopolysaccharides induced activation of microglia at birth and alteration of glutamatergic synapses in the adult offspring. Finally, neurons cultured from neonates born to inflamed mothers and cultured without microglia also displayed altered neuronal activity. CONCLUSION/SIGNIFICANCE: Our results demonstrate that prenatal inflammation is sufficient to induce synaptic alterations with delay. We propose that these alterations triggered by prenatal activation of microglia provide a cellular basis for the neuropsychiatric defects induced by prenatal inflammation.

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  • Microglia can contribute to synaptic plasticity in the adult CNS and in the context of the normal developing hippocampus.

    “Furthermore, microglia can contribute to synaptic plasticity in the adult CNS and, more recently, in the context of the normal developing hippocampus (Paolicelli et al., 2011; Pascual et al., 2011; Roumier et al., 2008).”

    From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Roumier et al., 2008

    The Discussion reports altered adult hippocampal synaptic function after prenatal microglial activation, and describes enhanced long-term potentiation in mice with a mutation affecting a microglial gene. The Results also describe microglia in the developing hippocampus, but the paper does not establish that microglia contribute to synaptic plasticity during normal hippocampal development; its functional findings concern mutation or inflammation. (LLM, conf=0.87)

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  • Multiple studies using different species document activation of microglia and astrocytes in response to maternal inflammation that leads to dysregulation in glutamate homeostasis.

    “Multiple studies using different species of animals document an activation of microglia and astrocytes in response to maternal inflammation that leads to dysregulation in glutamate homeostasis (Roumier et al., 2008; Weaver-Mikaere et al., 2013; Zhang et al., 2016).”

    From Neuroinflammation as a risk factor for attention deficit hyperactivity disorder (2019) · cites this paper as Roumier et al., 2008

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Authors
Roumier, A., Pascual, O., Béchade, C., Wakselman, S., Poncer, J.-C., Réal, E., Triller, A., & Bessis, A.
Affiliations
  • Inserm (FR)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Bessis, Alain
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2008-07-09
Volume
3
Issue
7
Pages
e2595
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0002595
PMC
PMC2440505
OpenAlex
W1986281170
Cited by
146
References
45
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 1 · 2022: 4 · 2021: 8 · 2020: 9 · 2019: 7 · 2018: 16 · 2017: 12 · 2016: 11 · 2015: 15 · 2014: 15 · 2013: 13 · 2012: 12
FWCI
3.08
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
Agence Nationale de la Recherche
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
prenatal inflammation, microglia, glutamatergic synapses, synaptic dysfunction, DAP12, Nasu-Hakola disease, maternal infection, lipopolysaccharide, AMPA receptors, IL-1β, interleukin-6, inducible nitric oxide synthase, neuropsychiatric disorders, cognitive impairment, microglia-neuron interaction
MeSH terms
Animals, Embryo, Mammalian, Female, Hippocampus, Inflammation, Mice, Transgenic, Mutation, Synaptic Transmission, Neurons, Pregnancy, Synapses, Microglia, Receptors, AMPA, Glutamic Acid, Adaptor Proteins, Signal Transducing, Mice

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