Neurodevelopmental and Behavioral Consequences of Serotonin System Disruption via Early Life Exposure to SSRI Antidepressants

Abstract

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring's neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. Studies in humans and experimental animal models shows that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can lead to abnormal emotional behaviors in adulthood, with a majority of the studies focusing on male offspring behavior. In this dissertation, we assessed whether SSRI-induced neurobiological and behavior changes occur in both sexes and whether these changes emerge in the juvenile period. In addition, we observed gene expression changes in the hippocampus related to metabolism and synaptogenesis. Given that, we hypothesized that the behavioral impacts following SSRI exposure may be driven, in part, by these processes. Juvenile offspring exposed to SSRIs in early life, regardless of sex, displayed increased anxiety-like behavior and altered social play. In adulthood, perinatal SSRI-exposed male and female offspring displayed increased passive coping in the Forced Swim Test but showed no differences in anxiety-like behavior. In addition to emotional behaviors, dams with a history of early-life SSRI exposure exhibited decreased maternal care, including diminished arched-back nursing, reduced licking and grooming of pups, and increased behavioral inconsistency. Alongside these behavioral changes, during infancy, we observed increased metabolic activity in the dentate gyrus of the hippocampus and decreased activity in the basolateral amygdala. During adulthood, the CA and dentate gyrus of the hippocampus in both sexes and the paraventricular nucleus of the hypothalamus in female offspring were more metabolically active in exposed offspring. We also observed differences in inter-correlations of limbic region COX activity in perinatal SSRI exposed and control offspring. Finally, a major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). As a G-protein coupled receptor (GPCR), it is an interesting potential therapeutic target, since most recently approved drugs in the central nervous system act on GPCRs. Data present here show that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together, these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms and metabolic changes that drive adverse effects of perinatal SSRI exposure and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia. Therefore, these data suggest that investigate the Bai3 network may be an exciting route as a potential therapeutic target for depression.