Maternal SSRI Exposure Results in Developmental and Long-Term Social Behavior Disruptions in Offspring.

Background: Six recent epidemiology studies found a significant association between maternal antidepressant (AD) use, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), and increased risk of autism spectrum disorder (ASD) in the offspring. The heightened risk of ASD diagnosis was independent of mothers’ depressive symptoms, indicating the risk is mediated by exposure to the drug. Two more studies reported a significant association with ASD and maternal AD use prior to but not during pregnancy, while another two reported no significant increase in ASD risk following maternal AD use. Thus, while on the balance more of these retrospective human studies implicated SSRI exposure as a risk factor, the debate would be strongly informed by explanatory studies in a model organism to identify whether mechanisms exist for long-term behavioral disruptions due to maternal SSRI use. Animal studies in particular allow for precise experimental control of exposures, and can provide clear indication as to whether transient SSRI exposure can alter long-term social behavior in placental animals.

Objectives: The objective of this study was to model in the rodent the recent human patient population findings to directly examine the risk of presenting ASD-relevant behaviors following maternal SSRI exposure during pregnancy and lactation and to elucidate molecular and cellular mechanisms in the brain.

Methods: Pregnant C57BL/6J female mice were exposed to the SSRI fluoxetine (FLX) via drinking water at a dose approximately equivalent to the maximum recommended human dose. The developmental and behavioral consequences in the offspring were examined, as well as cellular morphology and cell-specific transcriptional changes. Maternal FLX exposure began prior to breeding and continued through pregnancy and lactation until the pups were P14. To examine critical exposure periods, dams were also exposed only until birth (P0) or until E16 (equivalent to first trimester of human brain development). We examined possible interactive effects on behavior of FLX exposure and genetic susceptibility by exposing mothers of Celf6 mutants, which exhibit a partial ASD-like phenotype (Dougherty, Maloney et al. 2013).

Results: Compared with vehicle-exposed controls, maternal FLX exposure resulted in robust long-term social behavior disruptions. During early postnatal ages, FLX exposure robustly attenuated USV calls and decreased weight. Altered social behaviors were observed in FLX-exposed pairs during juvenile play. In adulthood, impaired sociability and robustly altered social dominance were observed in FLX-exposed mice. Only when FLX exposure extended to P14 were behaviors altered in the T-maze and marble burying task. In the genetically vulnerable line, FLX exposure and Celf6 mutation acted separately but in the same manner on developmental and long-term behaviors. Dendritic morphology and cell-specific gene expression were examined at ages coinciding with early social communicative deficits (P9) and later sociability and dominance changes (P60).

Conclusions: Maternal SSRI exposure in the C57BL/6J mouse leads to social communicative deficits in pups and long-term social behavior deficits. The influence of drug exposure on repetitive patterns of behavior may be dependent on age at exposure, specifically postnatal exposure through lactation. This study may have implications for the safety of antidepressant use in pregnant women and further research is needed.