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Altered extracellular mRNA communication in postpartum depression is associated with decreased autophagy

Abstract

We investigated whether extracellular RNA communication, which is a recently discovered mode of intercellular communication that is involved in a variety of important biological processes including pregnancy, is associated with postpartum depression (PPD). Extracellular RNA communication is increased during pregnancy and is involved in embryo implantation, uterine spiral artery remodeling, parturition, preterm birth, immunity, and the inflammatory response. Since immune anomalies are associated with PPD, we characterized the mRNA content of extracellular vesicles (EV) in a cohort of prospectively collected blood plasma samples at six time-points throughout pregnancy and the postpartum (2nd trimester, 3rd trimester, 2 weeks postpartum, 6 weeks postpartum, 3 months postpartum, and 6 months postpartum) in an academic medical setting from women who went on to develop PPD (N = 7, defined as euthymic in pregnancy with postpartum-onset depressive symptoms assessed by Edinburgh Postnatal Depression Scale ≥13 at any postpartum time point) and matched unaffected controls (N = 7, defined as euthymic throughout pregnancy and postpartum). Blood samples were available for all participants at the T2 and W6 timepoints, with fewer samples available at other time points. This analysis revealed that EV mRNA levels during pregnancy and the postpartum period were extensively altered in women who went on to develop PPD. Gene set enrichment analysis revealed that mRNAs associated with autophagy were decreased in PPD cases. In contrast, EV mRNAs from ribosomes and mitochondria, two organelles that are selectively targeted by autophagy, were elevated in PPD cases. Cellular deconvolution analysis discovered that EV mRNAs associated with PPD originated from monocytes and macrophages. Quantitative PCR analysis for four relevant genes in another cohort replicated these findings and confirmed that extracellular RNA levels are altered in PPD. We demonstrate that EV mRNA communication is robustly altered during pregnancy and the postpartum period in women who go on to develop PPD. Our work also establishes a direct link between reduced autophagy and PPD in patient samples. These data warrant investigating the feasibility of developing EV mRNA based biomarkers and therapeutic agents for PPD.

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Fig. 1: EV mRNA Communication is Disrupted in PPD.
Fig. 2: EV mRNA Changes in PPD during Pregnancy and the Postpartum Period.
Fig. 3: Cellular Deconvolution Analysis of EV mRNA.
Fig. 4: Quantitative PCR Validation of EV mRNA Levels in an Additional Cohort.

Data availability

The raw data will be made available via the NIMH Data Archive. In the meantime, the raw data is available upon request.

Code availability

R code for the analysis is available upon request.

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Acknowledgements

The authors would like to thank Ms. Ou Chen for isolating EV mRNAs and constructing sequencing libraries and Ms. Treva Rowley for the CD72 PCR analysis. We also thank Dr. Stephanie Hicks for providing advice on cellular deconvolution analysis and Ms. Samantha Meilman for assistance with randomizing the initial cohort and matching controls to cases.

Funding

This study was funded by the following NIH grants NIH-NIMH R01 MH112704, NIH-NIMH 1K23 MH110607, and NIH-NIAID T32 AI007417.

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LMO, JLP, and SS conceived the idea and designed the initial experiments. LMO, JLP, and MLS collected the samples, characterized the patients and selected the cohorts used in the study. SS performed the laboratory assays and bioinformatic analysis. Everyone was involved in data interpretation and writing the paper.

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Correspondence to Sarven Sabunciyan.

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JLP has served as a consultant for SAGE Therapeutics, Brii Biosciences, and Pure Tech Health. JLP has received an honorarium from Karuna Therapeutics for speaking to the company. JLP owns a patent entitled “Epigenetic Biomarkers of Postpartum Depression.” LMO, MLS, and SS have no biomedical financial interests or potential conflicts of interest to report.

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Osborne, L.M., Payne, J.L., Sherer, M.L. et al. Altered extracellular mRNA communication in postpartum depression is associated with decreased autophagy. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01794-2

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