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Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

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

Posted 01 Apr 2020
bioRxiv DOI: 10.1101/2020.03.31.019190 (published DOI: 10.1016/j.biopsych.2020.10.016)

Maternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders 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 mechanistic dissection. We performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring, an age comparable to mid adolescence in humans. We identify 266 unique genes differentially expressed (DE) 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. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1st or 2nd trimester MIA exposures, including for the top DE genes, PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring. Together, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

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