Placenta-derived exosomes mediate the intergenerational transmission of depression by regulating WNT2B /β-catenin signaling

Maternal depression during pregnancy adversely affects offsprings from infancy through adulthood. Placenta-derived exosomes (P _exo ) play crucial roles in maternal-fetal communication. This study investigates the involvement of P _exo in the intergenerational transmission of maternal depression and its underlying molecular mechanisms. P _exo were isolated from placental tissue of newborns exhibiting neurobehavioral development disorders due to maternal depression during pregnancy (depression P _exo , n = 90) and from healthy newborns (control P _exo , n = 79). Pregnant SD rats were administrated to depression P _exo (n = 6) or prenatal stress(n = 6). Behavior test, bioinformatics analyses, and molecular biology approaches were used to examine the effects of P _exo . Newborns from mothers with depression during pregnancy exhibited neurobehavioral development deficits. Depression P _exo inhibited hippocampal neuron proliferation in primary neuron cultures, resulting in the depressive-like behaviors and the reduced hippocampal neurogenesis in offspring. miRNA sequencing combined with RT- qPCR identified 10 differentially expressed miRNAs in depression P _exo , with miRNA-485-5p emerging as a key regulator of hippocampal neurogenesis. Expression of WNT2B/β-catenin signaling was significantly decreased in offspring exposed to depression P _exo or prenatal stress. WNT2B administration rescued depressive-like behavior and restored hippocampal neurogenesis impaired by depression P _exo . Thus, placenta-derived exosomal miRNAs and WNT2B signaling represent promising therapeutic targets to mitigate the intergenerational effects of maternal depression.