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

Abstract

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates Nicholas F. AbstractBackground: 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.Methods: 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. Results: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 1 st or 2 nd 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.Conclusions: Together, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

Neuron-Specific Chromosomal Megadomain Organization Is Adaptive to Recent Retrotransposon Expansions

“…The findings reported are also of interest from the viewpoint of the potential neurotoxic effects of ERV2-like transcripts and proteins in human and invertebrate neurons, including potential links to tau- and TDP-43 associated neurodegenerative disease ( 33–37 ), and a recent report on increased HERV activation in the adolescent non-human primate brain exposed to maternal immune activation during prenatal development ( 38 ). Interestingly, we observed enrichment for Human ERV2-like (HERV-K) repeat sequences in inter-autosomal Hi- C contact maps from human neurons, an effect driven primarily by loci with strong synteny with murine B 2 megadomains (Figure S12, S13), strongly suggesting that compartment-specific enrichment of ERV2 sequences occurs in parallel across different mammalian lineages.…”

“…Our study strongly suggests that the reorganization of higher order chromatin in adult cortical neurons tracks the dramatic expansion of IAPs and other ERV2 transposable elements in Mus musculus- derived inbred lines, as compared to the wild-derived SPRET/Eij inbred strain harboring the 1.5 million year evolutionarilyy divergent Mus spretus genome ( 18 ). Previous studies linked a small subset of these newly inserted ERV sequences to strain-specific differences in gene expression, pathogenic mutations and neomorphisms ( 31, 32 ). However, our findings point to much broader cell-type specific adaptations in genome organization and function, including a partial remodeling of the chromosomal interaction map in mature cortical neurons.…”