TY - JOUR
T1 - Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates
AU - Page, Nicholas F.
AU - Gandal, Michael J.
AU - Estes, Myka L.
AU - Cameron, Scott
AU - Buth, Jessie
AU - Parhami, Sepideh
AU - Ramaswami, Gokul
AU - Murray, Karl
AU - Amaral, David G.
AU - Van de Water, Judy A.
AU - Schumann, Cynthia M.
AU - Carter, Cameron S.
AU - Bauman, Melissa D.
AU - McAllister, A. Kimberley
AU - Geschwind, Daniel H.
N1 - Funding Information:
This project was supported by funding from the Amgen Scholars Foundation awarded to NP, an Autism Science Foundation summer undergraduate research grant awarded to NP, MJG, and DHG, and by National Institute of Mental Health Grant No. 5P50MH106438-04 (UC Davis Conte Center; principal investigator, CSC, project awarded to DHG) and Grant No. R01MH109912 (principal investigator, DHG). This work was supported by a Simons Foundation for Autism Research Bridge to Independence Award (to MJG), Stanley & Jacqueline Schilling Neuroscience Postdoctoral Research Fellowship ([to MLE]), Dennis Weatherstone Predoctoral Fellowship from Autism Speaks (Grant No. 7825 [to MLE]), the Letty and James Callinan and Cathy and Andrew Moley Fellowship from the ARCS Foundation (to MLE), a Dissertation Year Fellowship from the University of California Office of the President (to MLE), P50-MH106438 (to CSC), and the University of California Davis Research Investments in Science and Engineering Program (to AKM).
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - MIA
KW - Myelination
KW - Nonhuman primates
KW - Retrotransposition
KW - RNA-seq
KW - Synaptic connectivity
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U2 - 10.1016/j.biopsych.2020.10.016
DO - 10.1016/j.biopsych.2020.10.016
M3 - Article
AN - SCOPUS:85098631476
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
ER -