Genome-wide DNA Methylation Changes in a Mouse Model of Infection-Mediated Neurodevelopmental Disorders

Biol Psychiatry. 2017 Feb 1;81(3):265-276. doi: 10.1016/j.biopsych.2016.08.010. Epub 2016 Aug 12.

Abstract

Background: Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution.

Methods: Prenatal immune activation was induced by maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic acid in middle or late gestation. Following behavioral and cognitive characterization of the adult offspring (n = 12 per group), unbiased capture array bisulfite sequencing was combined with subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and quantitative real-time polymerase chain reaction analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. Gene ontology term enrichment analysis was used to explore shared functional pathways of genes with differential DNA methylation.

Results: Adult offspring of immune-challenged mothers displayed hyper- and hypomethylated CpGs at numerous loci and at distinct genomic regions, including genes relevant for gamma-aminobutyric acidergic differentiation and signaling (e.g., Dlx1, Lhx5, Lhx8), Wnt signaling (Wnt3, Wnt8a, Wnt7b), and neural development (e.g., Efnb3, Mid1, Nlgn1, Nrxn2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring's age and were markedly influenced by the precise timing of prenatal immune activation.

Conclusions: Prenatal viral-like immune activation is capable of inducing stable DNA methylation changes in the medial prefrontal cortex. These long-term epigenetic modifications are a plausible mechanism underlying the disruption of prefrontal gene transcription and behavioral functions in subjects with prenatal infectious histories.

Keywords: Autism; DNA methylation; Epigenetics; Maternal immune activation; Poly(I:C); Schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • CpG Islands
  • DNA Methylation*
  • Disease Models, Animal
  • Epigenesis, Genetic
  • Female
  • GABAergic Neurons / metabolism
  • Genome
  • Interpersonal Relations
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neurodevelopmental Disorders / chemically induced
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / immunology
  • Neurodevelopmental Disorders / metabolism*
  • Poly I-C
  • Prefrontal Cortex / metabolism*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / genetics*
  • Prenatal Exposure Delayed Effects / immunology
  • Prenatal Exposure Delayed Effects / metabolism*
  • Prepulse Inhibition / drug effects
  • Prepulse Inhibition / physiology
  • Wnt Signaling Pathway

Substances

  • Poly I-C