Nicholas F Page1, Michael J Gandal2, Myka L Estes3, Scott Cameron3, Jessie Buth4, Sepideh Parhami4, Gokul Ramaswami4, Karl Murray5, David G Amaral5, Judy A Van de Water5, Cynthia M Schumann5, Cameron S Carter6, Melissa D Bauman5, A Kimberley McAllister6, Daniel H Geschwind7. 1. Department of Psychiatry, Center for Autism Research and Treatment, Los Angeles, California; Department of Cell Biology and Neuroscience, Rutgers University-New Brunswick, Piscataway, New Jersey. 2. Department of Psychiatry, Center for Autism Research and Treatment, Los Angeles, California. 3. Center for Neuroscience, School of Medicine, University of California, Davis, Davis, California. 4. Department of Psychiatry, Center for Autism Research and Treatment, Los Angeles, California; Program in Neurobehavioral Genetics, Center for Autism Research and Treatment, Los Angeles, California. 5. Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California, Davis, Davis, California. 6. Center for Neuroscience, School of Medicine, University of California, Davis, Davis, California; Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California, Davis, Davis, California. 7. Department of Psychiatry, Center for Autism Research and Treatment, Los Angeles, California; Program in Neurobehavioral Genetics, Center for Autism Research and Treatment, Los Angeles, California; Department of Neurology, Center for Autism Research and Treatment, Los Angeles, California; Department of Human Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address: dhg@mednet.ucla.edu.
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.
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.
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