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

Afc can adopt either the fully extended or a turn conformation

We have synthesized by solution methods and fully characterized two sets of terminally protected peptides based on the tricyclic C-alpha,C-alpha-disubstituted glycine Afc. The conformational preferences of the Afc/Gly peptides were examined by FT-IR absorption and H-1 NMR techniques, while those of the Afc/TOAC peptides were primarily investigated by using fluorescence spectroscopy. The X-ray diffraction structure of an Afc derivative was also analyzed. The body of solution and crystal-state experimental data conclusively confirms previous findings that the Afc residue may either adopt the fully extended (C-5) or a turn conformation

New tools for the control of peptide conformation and supramolecular chemistry: Crown-carrier, C-alpha-methyl L-DOPA amino acids

The preferred conformation of five, terminally protected, model peptide series to the hexamer level, based on three novel crowned, C\u3b1-methyl L-DOPA amino acids combined with either L-Ala/Aib or Gly/Aib, were assessed in structure supporting solvents using FT-IR absorption, 1H NMR, and CD techniques. The FT-IR absorption spectra strongly suggest that the contribution of the crowned C\u3b1-tetrasubstituted residue to intramolecular H-bonding is equivalent to that of Aib and is much more significant than that of either L-Ala or Gly. In addition, the 1H NMR titrations and the CD patterns resemble those typically exhibited by (right-handed) 310-helical structures

Induced Axial Chirality in the Biphenyl Core of Linear and Cyclic Bip and \u3b2-2,2-Bip Short Peptides

M. Flegel, M. Fridkin, C. Gilon, and J. Slaninova Eds., Kenes International, Geneva, Switzerland, 2005, pp. 1007-1008