Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring

Biol Psychiatry. 2018 Apr 15;83(8):680-691. doi: 10.1016/j.biopsych.2017.09.030. Epub 2017 Nov 14.

Abstract

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.

Keywords: Epilepsy; GABA switch; KCC2; Maternal immune activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cerebral Cortex / physiology*
  • Disease Models, Animal
  • Embryo, Mammalian
  • Epilepsy / etiology*
  • Excitatory Postsynaptic Potentials / physiology*
  • Female
  • Inhibitory Postsynaptic Potentials / physiology*
  • K Cl- Cotransporters
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Pregnancy
  • Pregnancy Complications / immunology*
  • Prenatal Exposure Delayed Effects / etiology*
  • Receptors, Interleukin-1 Type I
  • Symporters
  • gamma-Aminobutyric Acid*

Substances

  • Receptors, Interleukin-1 Type I
  • Symporters
  • gamma-Aminobutyric Acid