MicroRNA as a potential mediator in maternal/fetal interaction in neurodevelopmental disorders
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The Developmental Origins of Health and Disease hypothesis (DoHaD) purposes that environmental stress exposure to the intrauterine and maternal systems at key developmental periods may lead to long-term impacts on the health of the offspring. Our previous mouse model study demonstrated that the combination of maternal serotonin receptor transporter (SERT) heterozygosity and prenatal stress exposure resulted in reduced social preference and increased repetitive behaviors in male offspring, compared to wild-type controls. Additionally, we identified three differentially expressed maternal microRNAs (mmu-miR-7684-3p, mmu-miR-5622-3p, mmu-miR-6900-3p) in the SERT-het/stress group, demonstrating the epigenetic changes in the miRNA profile at the time of pregnancy. To investigate the mechanistic role of the prenatal stress-associated miRNAs, they were replicated as oligonucleotide miRNA mimics and combined into a miRNA mix diluted to 50 ug/100 uL. C57Bl/6J pregnant mice were then injected with 100 uL on gestational day 6 (G6) and again on G14. Starting from post-natal day 60, offspring from injected and injection naive mice were behaviorally tested for social communication, repetitive behaviors, and other anxiety measures. Offspring displayed no differences in social interactions or repetitive grooming behaviors but, during open field testing, 18/23 (80%) of tested offspring from injected dams displayed spontaneous, and repetitive jumping directly into the wall of the chamber. They exhibited decreased duration within the center of the open field and this was corroborated by higher thigmotaxis. However, prenatally miRNA exposed offspring also displayed increased distance travelled during the elevated plus maze as well as longer duration spent on open arms than non-injected controls, suggesting differing anxiety-like phenotypes. These findings suggest maternal intravenous exposure to the three prenatal stress-related miRNA recapitulates specific behavioral patterns of hyperlocomotion and wall-directed repetitive behaviors independent of social ability and self-grooming behaviors.
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M.A.