title: Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM, U789, Laboratoire de Biologie Cellulaire de la Synapse, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Roumier
authors.forename: Olivier
authors.initials: O
authors.lastname: Pascual
authors.forename: Catherine
authors.initials: C
authors.lastname: Béchade
authors.forename: Shirley
authors.initials: S
authors.lastname: Wakselman
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Poncer
authors.forename: Eleonore
authors.initials: E
authors.lastname: Réal
authors.forename: Antoine
authors.initials: A
authors.lastname: Triller
authors.forename: Alain
authors.initials: A
authors.lastname: Bessis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000196:embryology* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018091:Receptors, AMPA; C484963:Tyrobp protein, mouse; D018698:Glutamic Acid