Prenatal serotonin depletion persistently disrupts social behavior and modulates ΔFosB and SERT expression in mice

Embryonic fluctuations in serotonin (5-HT) levels during pregnancy have been associated with maternal depression and linked to social deficits and neuropsychiatric disorders in offspring. This preclinical study examined the long-term effects of transient prenatal 5-HT depletion on social, anxiety-like, and depressive-like behaviors across development, and evaluated associated changes in serotonergic markers and neuronal activity in key brain regions. Pregnant C57BL/6 mice were administered the 5-HT synthesis inhibitor para-chlorophenylalanine (PCPA), or its vehicle, from gestational day 12.5 to 14.5. Maternal affect and caregiving behavior were assessed postnatally, and offspring of both sexes were evaluated for social interaction, compulsive behavior, locomotion, ultrasonic vocalizations, and helplessness during infancy, adolescence, and adulthood. Immunohistochemistry was performed in the offspring to assess serotonin transporter (SERT) and ΔFosB expression in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). PCPA administration did not significantly alter depressive- or anxiety-like behavior in the dams, nor did it significantly affect maternal caregiving. The offspring prenatally exposed to PCPA exhibited reduced social interaction and increased non-social behaviors compared to controls during adolescence and adulthood. Prenatal serotonin depletion also led to decreased SERT and ΔFosB expression in the mPFC and NAc, indicating disrupted serotonergic signaling and altered neuronal activity in mood- and reward-related brain regions. The findings suggest that even brief disruptions of serotonergic signaling during gestation can induce lasting social deficits and neurobiological alterations relevant to the pathophysiology of neurodevelopmental disorders.