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

Nicholas F. Page, Michael J. Gandal, Myka L. Estes, Scott Cameron, Jessie Buth, Sepideh Parhami, Gokul Ramaswami, Karl Murray, David G. Amaral, Judy A. Van de Water, Cynthia M. Schumann, Cameron S. Carter, Melissa D. Bauman, A. Kimberley McAllister, Daniel H. Geschwind

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - 2020

Keywords

  • MIA
  • Myelination
  • Nonhuman primates
  • Retrotransposition
  • RNA-seq
  • Synaptic connectivity

ASJC Scopus subject areas

  • Biological Psychiatry

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