Postnatal depression-associated breastmilk extracellular vesicles mediate intergenerational effects on offspring...

Postnatal depression (PND) is associated with offspring neurodevelopmental impairments, but the mechanisms remain unclear. Here, we identify an intergenerational pathway whereby maternal psychological state is encoded in breastmilk microRNAs (miRNAs) and transmitted to offspring via small extracellular vesicles (sEVs). Using cross-fostering models, we show that maternal depression disrupts newborn neuron maturation in the offspring hippocampal dentate gyrus (DG), causing cognitive deficits and depressive-like behaviors. Gastric administration of PND-derived breastmilk sEVs to healthy pups recapitulates these phenotypes. Mechanistically, PND-induced miRNAs are packaged into breastmilk sEVs and delivered to the offspring brain, where they suppress mGluR8 in supramammillary nucleus (SuM) neurons projecting to DG. This presynaptic mGluR8 deficiency drives a "high-frequency, low-amplitude" neuronal activation pattern. Inhibiting mammary sEV secretion or sequestering these miRNAs in offspring SuM neurons rescues the deficits. Our findings define a mechanism underlying PND-related offspring neurodevelopmental impairments and suggest a therapeutic target for interrupting the intergenerational transmission of maternal mental disorders.