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Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring.
Corradini, Irene; Focchi, Elisa; Rasile, Marco; Morini, Raffaella; Desiato, Genni; Tomasoni, Romana; Lizier, Michela; Ghirardini, Elsa; Fesce, Riccardo; Morone, Diego; Barajon, Isabella; Antonucci, Flavia; Pozzi, Davide; Matteoli, Michela.
Afiliação
  • Corradini I; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy; Institute of Neuroscience - National Research Council, Milan, Italy.
  • Focchi E; Institute of Neuroscience - National Research Council, Milan, Italy; Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
  • Rasile M; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy; Hunimed University, Rozzano, Italy.
  • Morini R; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy.
  • Desiato G; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy; University of Milano-Bicocca, Milan, Italy.
  • Tomasoni R; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy.
  • Lizier M; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy; Institute for Genetic and Biomedical Research - National Research Council, Milan, Italy.
  • Ghirardini E; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy; Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
  • Fesce R; Hunimed University, Rozzano, Italy; Neuroscience Center, Dipartimento di Scienze Teoriche e Applicate, Insubria University, Busto Arsizio, Italy.
  • Morone D; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy.
  • Barajon I; Hunimed University, Rozzano, Italy.
  • Antonucci F; Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
  • Pozzi D; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy; Hunimed University, Rozzano, Italy.
  • Matteoli M; Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Rozzano, Italy; Institute of Neuroscience - National Research Council, Milan, Italy. Electronic address: m.matteoli@in.cnr.it.
Biol Psychiatry ; 83(8): 680-691, 2018 04 15.
Article em En | MEDLINE | ID: mdl-29146047
BACKGROUND: The association between maternal infection and neurodevelopmental defects in progeny is well established, although the biological mechanisms and the pathogenic trajectories involved have not been defined. METHODS: Pregnant dams were injected intraperitoneally at gestational day 9 with polyinosinic:polycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses. RESULTS: Prenatal exposure to polyinosinic:polycytidylic acid causes an imbalanced expression of the Na+-K+-2Cl- cotransporter 1 and the K+-Cl- cotransporter 2 (KCC2). This results in delayed gamma-aminobutyric acid switch and higher susceptibility to seizures, which endures up to adulthood. Chromatin immunoprecipitation experiments reveal increased binding of the repressor factor RE1-silencing transcription (also known as neuron-restrictive silencer factor) to position 509 of the KCC2 promoter that leads to downregulation of KCC2 transcription in prenatally exposed offspring. Interleukin-1 receptor type I knockout mice, which display braked immune response and no brain cytokine elevation upon maternal immune activation, do not display KCC2/Na+-K+-2Cl- cotransporter 1 imbalance when implanted in a wild-type dam and prenatally exposed. Notably, pretreatment of pregnant dams with magnesium sulfate is sufficient to prevent the early inflammatory state and the delay in excitatory-to-inhibitory switch associated to maternal immune activation. CONCLUSIONS: We provide evidence that maternal immune activation hits a key neurodevelopmental process, the excitatory-to-inhibitory gamma-aminobutyric acid switch; defects in this switch have been unequivocally linked to diseases such as autism spectrum disorder or epilepsy. These data open the avenue for a safe pharmacological treatment that may prevent the neurodevelopmental defects caused by prenatal immune activation in a specific pregnancy time window.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complicações na Gravidez / Efeitos Tardios da Exposição Pré-Natal / Córtex Cerebral / Potenciais Pós-Sinápticos Excitadores / Epilepsia / Potenciais Pós-Sinápticos Inibidores / Ácido gama-Aminobutírico Tipo de estudo: Prognostic_studies Limite: Animals / Pregnancy Idioma: En Revista: Biol Psychiatry Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complicações na Gravidez / Efeitos Tardios da Exposição Pré-Natal / Córtex Cerebral / Potenciais Pós-Sinápticos Excitadores / Epilepsia / Potenciais Pós-Sinápticos Inibidores / Ácido gama-Aminobutírico Tipo de estudo: Prognostic_studies Limite: Animals / Pregnancy Idioma: En Revista: Biol Psychiatry Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Itália