Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function

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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 (DAP12KI mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12KI 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 DAP12KI microglia overexpress genes far IL1β, 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 culture 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 neuropyschiatric defects induced by prenatal inflammation. © 2008 Roumier et al.

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APA

Roumier, A., Pascual, O., Béchade, C., Wakselman, S., Poncer, J. C., Réal, E., … Bessis, A. (2008). Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function. PLoS ONE, 3(7). https://doi.org/10.1371/journal.pone.0002595

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