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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.

JL Payne and ZA KaminskyPostpartum depression (PPD) affects B10–18% of women in the general population and results in serious consequences to boththe mother and offspring. We hypothesized that predisposition to PPD risk is due to an altered sensitivity to estrogen-mediatedepigenetic changes that act in a cell autonomous manner detectable in the blood. We investigated estrogen-mediated epigeneticreprogramming events in the hippocampus and risk to PPD using a cross-species translational design. DNA methylation profileswere generated using methylation microarrays in a prospective sample of the blood from the antenatal period of pregnant mooddisorder patients who would and would not develop depression postpartum. These profiles were cross-referenced with synteniclocations exhibiting hippocampal DNA methylation changes in the mouse responsive to long-term treatment with 17b-estradiol(E2). DNA methylation associated with PPD risk correlated significantly with E2-induced DNA methylation change, suggesting anenhanced sensitivity to estrogen-based DNA methylation reprogramming exists in those at risk for PPD. Using the combined mouseand human data, we identified two biomarker loci at the HP1BP3 and TTC9B genes that predicted PPD with an area under thereceiver operator characteristic (ROC) curve (area under the curve (AUC)) of 0.87 in antenatally euthymic women and 0.12 in areplication sample of antenatally depressed women. Incorporation of blood count data into the model accounted for thediscrepancy and produced an AUC of 0.96 across both prepartum depressed and euthymic women. Pathway analysesdemonstrated that DNA methylation patterns related to hippocampal synaptic plasticity may be of etiological importance to PPD.Molecular Psychiatry advance online publication, 21 May 2013; doi:10.1038/mp.2013.62Keywords: biomarker; DNA methylation; estrogen; HP1BP3; postpartum depression; TTC9BINTRODUCTIONPostpartum depression (PPD) occurs in approximately 10–18% ofwomen and results in significant morbidity in both mother andchild, with offspring risks including low self-esteem, low intellec-tual skills, child abuse and infanticide.