Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

Biol Psychiatry. 2021 May 1;89(9):896-910. doi: 10.1016/j.biopsych.2020.10.016. Epub 2020 Nov 2.

Abstract

Background: Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates.

Methods: We performed RNA sequencing across psychiatrically relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus) and primary visual cortex for comparison from 3.5- to 4-year-old male MIA-exposed and control offspring-an age comparable to mid adolescence in humans.

Results: We identify 266 unique genes differentially expressed in at least one brain region, with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Although we observed temporal and regional differences, transcriptomic changes were shared across first- and second-trimester exposures, including for the top differentially expressed genes-PIWIL2 and MGARP. In addition to PIWIL2, several other regulators of retrotransposition and endogenous transposable elements were dysregulated following MIA, potentially connecting MIA to retrotransposition.

Conclusions: Together, these results begin to elucidate the brain-level molecular processes through which MIA may impart risk for psychiatric disease.

Keywords: MIA; Myelination; Nonhuman primates; RNA-seq; Retrotransposition; Synaptic connectivity.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins
  • Behavior, Animal*
  • Disease Models, Animal
  • Female
  • Humans
  • Poly I-C
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Primates
  • Transcriptome

Substances

  • Argonaute Proteins
  • PIWIL2 protein, human
  • Poly I-C