Maternal serotonin transporter genotype influences offspring’s anxiety-like behavior through prenatal and early postnatal routes

Maternal serotonin transporter (5-HTT) genotype has been linked to offspring’s risk for neuropsychiatric disorders, yet the contribution of prenatal versus early postnatal routes remains unresolved. We combined a 5-HTT−/− rat model with a fostering procedure to disentangle these effects. 5-HTT+/− offspring genotype was kept constant by crossing 5-HTT−/− or 5-HTT+/+ dams with males of opposite genotypes. Prenatally, compared with 5-HTT+/+ dams, 5-HTT−/− dams produced smaller embryos with impaired serotonergic maturation. Their placentas exhibited alterations in serotonergic-related signaling. Postnatally, 5-HTT−/− dams exhibited reduced licking and grooming. Adult offspring from 5-HTT−/− dams showed lower anxiety-like behavior alongside altered corticosterone recovery following stress and elevated infralimbic Gad67 expression relative to offspring from 5-HTT+/+ dams. To dissociate prenatal from postnatal influences, offspring were cross-fostered with genotype-mismatched dams. Under cross-fostering, offspring from 5-HTT−/− dams exhibited a higher serotonin/tryptophan ratio and reduced Bdnf isoform VI expression in the medial prefrontal cortex compared to offspring from 5-HTT+/+ dams. Independent of biological dam genotype, cross-fostering reduced body weight, increased anxiety-like behavior, and downregulated HPA-axis- and GABA/glutamatergic-related signaling. Here, we demonstrate that maternal 5-HTT genotype shapes offspring’s anxiety-like behavior through combined prenatal and early postnatal effects, highlighting the intertwined roles of maternal genetics and environment in neuropsychiatric disorders' pathophysiology.