Prenatal Activation of Microglia Induces Delayed Impairment of Glutamatergic Synaptic Function

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

Synthesis of terminally protected 9-amino-4,5-diazafluorene-9-carboxylic acid, the first rigid, transition-metal receptor, C-alpha,alpha-disubstituted glycine

N-tert-Butyloxycarbonyl-9-amino-4,5-diazafluorene-9-carboxylic acid methyl ester, Boc-Daf-OMe, the first C-alpha,C-alpha-disubstituted glycine containing a rigid bipyridine ligand in a totally controlled spatial situation relative to the C-alpha atom of the amino acid, and a potential building block for the synthesis of peptide supramolecular devices, has been synthesized by acylation of the anion of N-benzyl-4,5-diazafluorene-9-methylenamine, followed by N-protection. Hydrazinolysis of the ester function afforded the hydrazide Boc-Daf-NHNH2, a key precursor for the acylazide coupling method

beta-Homo-peptides built from beta-2,2-HBip, a biphenyl-substituted 3-amino-2,2-dimethylpropanoic acid

A novel beta(2,2)-gem-disubstituted amino acid, beta(2,2)-HBip, has been synthesized by alpha,alpha-bis-alkylation of alkyl cyanoacetates with 2,2'-bis-(bromomethyl)-1,1'-diphenyl, followed by NaBH4/CoCl2 reduction of the cyano group. Both its C- and N-protected derivatives have been obtained. A slow interconversion at the NMR time scale is generally observed between the two enantiomers of the conformationally labile beta(2,2)-HBip residue. The homo-peptides Boc-(beta(2,2)-HBip)(n)-OMe have been prepared in solution by the EDC/HOBt coupling method to the hexamer level and a preliminary conformational analysis has been performed by H-1 NMR and FT-IR absorption techniques